Kinase-targeted cancer therapies: progress, challenges and future directions
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The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.
KeywordsKinases Kinase inhibition Small-molecule drugs Cancer Oncology
Abelson murine leukemia viral oncogene
Abelson murine leukemia viral oncogene homolog 1
Protein kinase B
Anaplastic lymphoma kinase
Ataxia telangiectasia mutated
- Aur A & B
Aurora kinase A & B, B-Raf
Bruton agammaglobulinemia tyrosine kinase
Checkpoint kinase 1
Proto-oncogene c-Kit or Mast/stem cell growth factor receptor
Proto-oncogene tyrosine-protein kinase
Cytoplasmic tyrosine kinase
c-Yes proto-oncogene (pp62c-Yes)
Epidermal growth factor receptor
V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog
Feline sarcoma oncogene
Fibroblast growth factor receptors
- Flt3, Flt-4
Fms-like tyrosine kinase 3, 4
Human epidermal growth factor receptor-2
Insulin-like growth factor 1 receptor
Janus kinase 2
V-Kit hardy-zuckerman 4 feline sarcoma viral oncogene homolog
Mitogen-activated protein kinases
MEK kinase gene
Metastatic renal cell carcinoma
Mammalian target of rapamycin
Nuclear factor kappa-light-chain-enhancer of activated B cells
Platelet-derived growth factor receptors
Platelet-derived growth factor receptor α
Platelet-derived growth factor receptor β
Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
Phosphatidylinositol-3, 4, 5-triphosphate,
Protein kinase Ci
Phosphatase and tensin homolog
Rho-associated, coiled-coil-containing protein kinase 1
Recepteur d’Origine Nantais
Ribosomal protein kinase 2
Receptor tyrosine kinase
- S/T Kinase
Ribosomal protein S6 kinase
Sodium/glucose cotransporter 1
A small hairpin RNA
Sphingosine kinase 1
Proto-oncogene tyrosine-protein kinase c
Serine/threonine kinase 11 or liver kinase B1
Tropomyosin-related kinase B
Vascular endothelial growth factor receptor 2
Vascular endothelial growth factor receptors
List of FDA-approved kinase inhibitors and their drug targets
Crizotinib, Ceritinib, Alectinib, Brigatinib
Bosutinib, Dasatinib, Imatinib, Nilotinib, Ponatinib
Palbociclib, Sorafenib, Ribociclib
Gefitinib, Erlotinib, Lapatinib, Vandetanib, Afatinib, Osimertinib
Axitinib, Gefitinib, Imatinib, Lenvatinib, Nintedanib, Pazopanib, Regorafenib, Sorafenib, Sunitinib
Bosutinib, Dasatinib, Ponatinib, Vandetanib
Axitinib, Lenvatinib, Nintedanib, Regorafenib, Pazopanib, Sorafenib, Sunitinib
Role of kinases in cancer
Kinase discovery and development timeline
Types of kinase inhibitors
Classification of small molecule kinase inhibitors
Class of Kinase Inhibitor
Mechanism of Action
Competes for the substrate and binds in the ATP-binding pocket of the active conformation
Bosutinib, Cabozantinib, Ceritinib, Crizotinib, Gefitinib, Pazopanib, Ruxolitinib, Vandetanib
Type II inhibitors bind to the DFG-Asp out protein kinase conformation, which corresponds to an inactive enzyme form
Imatinib, Sorafenib, Axitinib, Nilotinib
Type III (Allosteric Inhibitor)
Occupy a site next to the ATP-binding pocket so that both ATP and the allosteric inhibitor can bind simultaneously to the protein.
Type IV (Substrate Directed Inhibitors)
Undergo a reversible interaction outside the ATP pocket and offer selectivity against targeted kinases
Type V (Covalent Inhibitor)
Bind covalently (irreversible)to their protein kinase target
Afatinib, Ibrutinib, HK1–272
Type I kinase inhibitors
Type I kinase inhibitors represent ATP-competitors that mimic the purine ring of the adenine moiety of ATP. Functionally, they interact with the conformational phosphorylated active catalytic site of the kinases. These kinase inhibitors bind to the active conformational site and alter the structural conformation otherwise favorable to phosphotransfer [98, 99]. Type I inhibitors usually contain a heterocyclic ring system that occupies the purine binding site, where it serves as a scaffold for side chains that occupy adjacent hydrophobic regions . These hydrophilic regions of the enzyme occupied by the ribose moiety of ATP may be used to exploit the solubility of the drugs or other active compounds . To date, many Type I kinase inhibitors for the treatment of cancer have been approved by the FDA viz. bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, ruxolitinib, sunitinib, and vemurafenib. Apart from the large-scale clinical success, Type I kinase inhibitors also come with adverse side-effects. Type I inhibitors display an inclination for low kinase selectivity as the targeted ATP pocket is conserved through the kinome; therefore, increasing the potential for off-target side effects. This little selectivity for targeted kinases may result in cardiotoxicity and possible deterioration in cardiac function [101, 102].
Type II kinase inhibitors
Type II kinase inhibitors act by targeting the inactive conformation of kinases and interact with the catalytic site of the unphosphorylated inactive conformation of kinases . Type II kinase inhibitors exploit new interactions inside the lipophilic pocket derived from the change of confirmation of the phenylalanine residue of the “Asp-Phe-Gly (DFG)” N-terminal loop conformation of kinases [16, 103]. These inhibitors interact reversibly with the target kinase which leads to the formation of single or multiple hydrogen bonds with the protein in the ‘hinge region’ and also causes extra interactions in the open DFG-out conformation [98, 103]. These lipophilic interactions have a high degree of selectivity towards unwanted kinases affecting an increase in the safety profile of Type II kinase inhibitors. Type II inhibitors also display a high conservation of distinctive H-bond pattern between the inhibitor and the glutamic and aspartic acids of the kinase [98, 104]. Due to the exclusivity of inactive protein kinase conformations, it was theorized than type II kinase inhibitors would be more selective. However, there is considerable overlap of selectivity between type I and type II inhibitors. The discovery of Type II kinase inhibitors such as imatinib and sorafenib was serendipitous, and it wasn’t until much later that their mode of action was discovered. The role of imatinib in the consequent development of small molecule protein kinase inhibitors cannot be overstated. All Type II inhibitors share a similar pharmacophore and hydrogen bonds that interact with DFG-out kinase conformational structure as revealed by the discovery of the Type II kinase inhibitor co-crystal structure . Since canonical ATP-binding sites of activated kinases, the target sites of Type I inhibitors, do not share these features, this pocket is conserved to a lesser extent across the kinome, and hence promises better prospects for the rational design of selective inhibitors [100, 103]. Overall, Type II kinase inhibitors display high selectivity towards kinase inhibition as compared to Type I kinase inhibitors along with the profound impact on cellular activity.
Type III or allosteric inhibitors
The third class of kinase inhibitors bind outside the catalytic domain/ATP-binding site and modulates kinase activity in an allosteric manner. Some authors have divided the allosteric inhibitors into two subtypes where type A inhibitors bind to an allosteric site next to the adenine-binding pocket whereas the type B inhibitors bind elsewhere . Overall, Allosteric or Type III inhibitors exhibit the highest degree of target kinase selectivity as they exploit binding sites and physiological mechanisms that are exclusive to a particular kinase . With respect to ATP, these drugs are steady-state noncompetitive or uncompetitive inhibitors because ATP cannot prevent their interaction with the target kinase. One of the earliest allosteric inhibitors was CI-1040, an orally active, highly specific, small-molecule inhibitor of the MEK1/MEK2 pathway . A recent chemical proteomics study confirms the allosteric activity of type III inhibitors as they showed a higher selectivity, but also stated that these are special cases as most of them are designated MEK1/2 inhibitors that bind to a particular cavity adjacent to the ATP-binding site . Another allosteric kinase inhibitor GnF2 binds to the myristate binding site of BCR–ABL1 . GnF2 also displays sound IL-3 reversible anti-proliferative and apoptotic effect on two mutants identified as E255V and Y253H . Likewise, TAK-733 binds to the MEK1-ATP complex in the gate area and the back cleft adjacent to the ATP-binding pocket; however, it cannot bind to the adenine pocket owing to its occupation by ATP . Other examples include RO0281675 and analogs thereof [111, 112]. Overall, targeting kinases using allosteric inhibitors is thought to be a crucial approach for overcoming hurdles in kinase inhibitor research, such as limited selectivity, off-target side effects, and drug resistance. In future, more active and target specific allosteric inhibitors will be discovered as larger stress is placed on cell-based assays in which kinases are explored in their native cellular context.
These are also called Type IV kinase inhibitors and undergo a reversible interaction outside the ATP pocket, located in the kinase substrate-binding site. These inhibitors don’t compete with ATP and offer a higher degree of selectivity against targeted kinases . Substrate-directed inhibitors include ATP-noncompetitive inhibitors such as ON012380 which are targeted against Philadelphia chromosome-positive leukemias . More importantly, ON012380 was found to override imatinib resistance at physiologically relevant concentrations of < 10 nM .
Type V or covalent inhibitors
The covalent kinase inhibitors form an irreversible covalent bond with the kinase active site and target a catalytic nucleophile cysteine within the active site of the enzyme [116, 117]. The chemical rationale for developing Type V inhibitors is based on exposed cysteine side chain in the ATP site which can be targeted for covalent reaction with a drug candidate with an electrophilic Michael acceptor in the right position [118, 119]. This type of kinase inhibition takes place via trapping of a solvent-exposed cysteine residue either by SN2 displacement of a leaving group or by reacting with a Michael acceptor incorporated within the kinase inhibitor [113, 120, 121]. Covalent inhibitors target respective kinase by formation of a rapidly reversible collision complex followed by an irreversible enzyme-inhibitor complex . Afatinib (targets EGFR (ErbB1), ErbB2, and ErbB4) and ibrutinib are currently FDA-approved drugs that form a covalent bond with their target kinase. Afatinib, unlike the first-generation EGFR-TKIs such as gefitinib and erlotinib, is a mutant-selective EGFR inhibitor with low toxicity profile despite its irreversible mechanism . Similar to Afatinib, ibrutinib also targets mutant-EGFR kinase with a distinct binding conformation . Both of these kinase inhibitors initiate Michael reaction with the addition of a nucleophile (the -SH of cysteine) to an α, β unsaturated carbonyl compound . C481 within hinge region of the Bruton tyrosine-protein kinase is hypothesized to form a covalent link with ibrutinib . A recently approved kinase inhibitor, neratinib (HKI-272), inhibits Herceptin-2 (HER-2), and prevents recurrence in patients with early-stage HER2-positive breast cancer . Overexpression of HER-2 is seen in 25–30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Likewise, CL-387785, a covalent inhibitor, overcomes resistance caused by T790 M mutation of the epidermal growth factor receptor (EGFR) . These kinase inhibitors also display an extended dissociation half-life which minimizes off-target side effects . Other advantages include prolonged pharmacodynamics, suitability for rational design, high potency, and ability to validate pharmacological specificity through mutation of the reactive cysteine residue . The approved covalent kinase inhibitors (Ibrutinib, Afatinib, and Neratinib) have shown that small molecules containing weak reactive electrophiles can be mutant specific in action with low toxicity. These kinase inhibitors have initiated resurgence of interest in covalent inhibitors, and feature an acrylamide functionality to specifically target the cysteine side chains of kinases. Example include a recent study showing nine irreversible EGFR and two BTK inhibitors with higher kinase inhibitory selectivity than reversible compounds . The Type V or covalent kinase inhibitors have substantial potential for exploration as 200 different kinases have a cysteine chain located near the ATP pocket.
Biochemically, kinase inhibitors are classified according to the activation state of the protein kinase target including the nature of DFG-Asp (active in, inactive out), the C-helix (active in, inactive out), and the regulatory spine (active linear, inactive distorted). Apart from type III or allosteric inhibitors, all the FDA-approved kinase inhibitors form hydrogen bonds with one or more hinge residues. Overall, most kinase inhibitors form: (i) hydrophobic contacts with catalytic spine residues; (ii) contact with the RS3 R-spine residue within the C-helix; (iii) interaction with the gatekeeper residue; and (iv) residues that occur just before the DFG-D of the activation segment [94, 129]. The following section briefly discusses the biochemical mechanism of action of FDA-approved kinase inhibitors.
Frequent mutations in various protein kinases present specific kinase inhibition as a therapeutically relevant approach in oncology. Kinase inhibitors have evolved to target many different regulatory and inhibitory mechanisms. There are various mechanisms by which kinase inhibitors bind to their target kinases broadly classified into kinase inhibitors that bind either covalently or non-covalently to or around the ATP binding site. Primarily, kinases bind with ATP in a cleft between the N- and C-terminal lobes of the kinase domain. In this domain, the adenine group of ATP is bound by two hydrophobic surfaces and interact via hydrogen bonds to the connector of two lobes, called the “hinge region” [130, 131, 132]. The cleft of ATP contains various elements such as the flexible activation loop (A-loop), along with closed conformations which are responsible for the catalytic activity of the kinase [133, 134]. The active or inactive state of the protein kinase is determined by the position of the A-loop, including the DFG motif at its N-terminal, which has various conformations [28, 98, 134, 135]. The only component of kinases that does not vary between the active and inactive states is the catalytic loop. The active state of the protein kinase when the Asp in the DFG motif coordinates one magnesium ion, which prepares the phosphates of ATP for the transfer of the phosphoryl group. The Phe in the DFG motif packs under the helix-C positioning both helix-C and A-loop for catalysis [98, 133, 136]. Protein kinases return to their inactive conformation once kinase transfers the phosphoryl group from ATP to tyrosine, serine or threonine of the substrate protein. This process also involves the returning of the A-loop to the closed position by the change of A-loop from the DFG-in to the DFG-out conformation [98, 137, 138]. However, ribose binding and the phosphate binding site of ATP usually remains unexplored by the majority of kinase inhibitors [134, 139]. Based on the biochemical mechanisms of action, kinase inhibitors are categorized as covalent and non-covalent kinase inhibitors. The non-covalent kinase inhibitors are classified into those who either bind or do not bind to the hinge region of the kinase . The DFG-in or Type I kinase inhibitors bind to hinge region and represent the vast majority of non-covalent kinase inhibitors . In these kinase inhibitors, the Asp in the DFG motif coordinates the phosphates of ATP, and the Phe in the DFG motif stabilizes the position of helix-C and the A-loop for catalysis . However, the ATP-binding pocket is highly preserved among members of the kinase family, and it is hard to find highly selective Type I kinase inhibitors. Moreover, the pre-clinical to clinical translation of Type I kinase inhibitors is hindered as they compete with high levels of intracellular ATP leading to a discrepancy between biochemical and cellular analysis. Contrary to the Type I inhibitors, Type II inhibitors bind to the DFG-out confirmation of kinases. These inhibitors induce a conformational shift in the target enzyme such that the target kinase is no longer able to function. Type II inhibitors use an additional hydrophobic pocket adjacent to the ATP site exposed by the movement of A-loop from DFG-in to DFG-out conformation . This gives the Type II inhibitors higher selectivity as they recognize novel regions of the active cleft outside the highly conserved ATP-binding site. Like Type II kinase inhibitors, the allosteric inhibitors or Type III inhibitors also display high selectivity as they explore binding sites and regulatory mechanisms that are unique to a particular kinase. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. Like Type II inhibitors, they also induce the DFG-out confirmation and move phenylalanine side chain to a new position [98, 99]. Examples include compounds such as CI-1040, which inhibit MEK kinase by occupying a pocket adjacent to the ATP-binding site . Interestingly, exploration of allosteric kinase inhibitors also helps to recognize unique kinase activation targets, which could be explored for therapeutic intervention in other diseases states. Recently, there has been an increased interest in the development of irreversible (covalent) kinase inhibitors that form covalent bonds with cysteine or other nucleophilic residues in the ATP-binding pocket. These inhibitors have typically been developed by incorporation of an electrophilic moiety into an inhibitor that already possesses submicromolar binding affinity to the target of interest. The covalent kinase inhibitors bind to a cysteine residue in or around the active site, thus preventing the binding of ATP to the protein kinase [117, 127]. These kinase inhibitors undergo the “Michael reaction”, which is a reaction that triggers the addition of a nucleophile, such as a cysteine, to an α, β unsaturated carbonyl functionality. Nucleophile additions cause the formation of adducts at the electrophilic β-position and inactivate kinases by irreversibly blocking the binding of ATP to kinase . These kinase inhibitors are highly selective as they overcome endogenous ATP competition and target a specific cysteine at the corresponding position in a kinase. Various covalent kinase inhibitors target kinases such as BTK , Fes , VEGF-R2 , and RSK2  through their ability to bind to a cysteine residue.
Recent clinical developments
Traditional cancer therapies follow palliative as well as off-targeted approaches in oncology. In contrast, kinase inhibitors symbolize a class of targeted cancer therapeutic agents with limited nonspecific toxicities. So far, 28 inhibitors with activity targeted to one or multiple kinases have been approved for clinical use. With over 500 members, the kinase family has received a high degree of attention from academic researchers as well as pharmaceutical industries . After the clearance of possible hindrances, owing to the high degree of active site similarities and possible off-target activity, kinase inhibitors have gained scientific limelight [21, 24, 78, 148, 149]. In a 13-year summary of targeted therapies including kinase inhibitors, the clinical success rate of kinase inhibitors was superior to other cancer therapies [150, 151]. Nevertheless, this clinical success does come with exceptions; attempts to control cytotoxicity during treatment, particularly with sunitinib and EGFR/VEGF-system targeting drugs have yielded disappointing results [152, 153, 154, 155]. Overall, during the last 5 years, Aurora kinases , casein kinase II , cyclin-dependent kinases , focal adhesion kinase , protein kinase B , phosphatidylinositol 4,5-bisphosphate 3-kinase delta and gamma , polo-like kinase I , tyrosine-protein kinase SYK , high affinity nerve growth factor receptor family  and Wee1-like protein kinase  have been targeted in Phase I clinical trials. Although recent developments have shown Aurora kinases as major new targets in kinase inhibitor development [166, 167]. After initial hurdles, two compounds palbociclib and ribociclib have passed the phase III clinical trials and are in clinical use .
Recent kinase developments include precision therapy based on tumor genomic data. The ability to perform genetic studies of tumors and follow-up treatment decisions based on the identification of tumorigenesis drivers has resulted in significant benefits for patients in need of effective systemic therapy. The detailed information regarding all the clinical trials is out of the scope of this mini-review; however, a few important developments are highlighted. A small number of small molecule tyrosine kinase inhibitors have recently received FDA approval for treatment of non-small cell lung cancer (NSCLC) with EGFR mutations or ALK translocations . Afatinib, a second-generation, non-competitive kinase inhibitor targeting all members of the ErbB family of receptors (also known as Her-2/neu) was approved in 2013 as frontline therapy for NSCLC patients with EGFR-deletion 19 and L858R mutations . Despite several challenges that need to be overcome, reviewed in [171, 172], precision medicine has yielded important dividends for patients with advanced cancers . In order to counter currently undruggable targets and acquired resistance, immunotherapy has gained widespread recognition in recent years . Additionally, kinase targeted antibody therapy for hematological malignancies, and solid tumors have become established over the past 20 years. Key examples of antibody constructs targeting kinases include Trastuzumab and T-DM1 (targeting ERBB2/HER2) in breast and bladder cancer [175, 176], Bevacizumab (targeting VEGF) in ovarian, metastatic colon cancer and glioblastoma , Cetuximab, Panitumumab and necitumumab (targeting EGFR) in colorectal cancer and NSCLC . Other experimental candidates include scFv, affibody and minibody (ERBB2/HER2 and FGFR1) [179, 180, 181, 182], Protein–Fc (VEGFR1 and VEGFR2)  and Intact IgG (EGFR, ERBB2, and VEGF) in breast and lung cancer studies. Also, there is an increased development of PI3K and mTOR inhibiting compounds. Dual PI3K/mTOR inhibitors in advanced clinical trials include NVP-BEZ235 (glioblastomas) , XL765 (breast cancer) , GDC0980 (mRCC) , PF04691502 (breast cancer) , GSK2126458 (colorectal, breast, non-small cell lung, and pancreatic cancers) , Quinacrine (various leukemias) [189, 190] and PKI587 (advanced solid malignancies) . Also, buparlisib and idelalisib, both PI3K inhibitors, have entered phase III clinical trials [192, 193]. In line with PI3K/mTOR inhibitors, various kinase inhibitors have entered into clinical trials for gastrointestinal cancers , thyroid carcinoma , breast cancer , and endocrine tumors . Many previously approved kinase inhibitors are being tested in clinical trials against BRAF and cyclin-dependent kinases 4/6 mutations [20, 99]. BRAF somatic mutation, particularly BRAF V600E/K, drive tumorigenesis through constitutive activation of the downstream MAPK pathway . Multiple drugs including vemurafenib, dabrafenib, PLX3603, ARQ736, CEP-32496, BMS-908662, BGB283, encorafenib in combination with other chemotherapies are being targeted for BRAF-mutated cancers . It is now suggested that dabrafenib, a selective BRAF inhibitor may target other kinases indicating polypharmacology (that is, drugs that act on more than one target) . A paper published by Klaeger and colleagues explains the potential of 243 clinically evaluated kinase drugs . Although multiple new kinases have been targeted during the last 5 years, a large share of the cancer kinome is still untargeted. Furthermore, use of these targeted therapies is not without limitations. Reservations on the use of kinase inhibitors include the development of resistance and the lack of tumor response in the general population and these constraints still need to be resolved.
Natural bioactives as kinase inhibitors
Furthermore, myricetin has been reported to target Akt to inhibit cell transformation and proliferation by directly binding to the ATP-binding site of Akt . Similar effects are also exhibited by curcumin , quercetin [234, 235], green tea molecules , anthocyanins  and other polyphenols [238, 239, 240]. Hyperactivity of cyclin-dependent kinases (CDKs) is one of the key mechanisms underlying tumorigenesis . The overexpression of CDKs is inhibited by various small molecule compounds [242, 243, 244, 245, 246]. Likewise, hyperactivity of mTOR pathway is also downregulated by natural compounds [229, 247, 248, 249]. The mTOR pathway is a critical effector in cell-signaling pathways and is commonly deregulated in human cancers. Furthermore, small molecule compounds also inhibit the activity of polo-like and Aurora kinases [207, 210, 250, 251]. B-Raf kinases, key kinases intimately involved in cancer cell proliferation , are also inhibited by natural plant compounds such as curcumin, luteolin, quercetin and ursolic acid [253, 254]. Finally, the overexpression of oncogenic lipid kinases such as PI3K and SK1 is also mitigated by small molecule bioactives. More than 30% of various solid tumor types were recently found to contain mutations in PI3K . Well explored bioactive molecules such as resveratrol , curcumin , quercetin  and green tea polyphenols  inhibit PI3K pathway. Similar to the parent compounds, metabolites of bioactives also inhibit PI3K pathway . Sphingosine kinase 1 (SphK1) is also an important component of carcinogenesis as it converts the proapoptotic lipids ceramide and sphingosine into the anti-apoptotic lipid sphingosine-1-phosphate . Inhibition of SphK1 is exhibited by few chelating bioactives [260, 261, 262]. Oncogenic kinases are vital proteins that couple extracellular signals with intracellular signaling pathways, which contribute to all stages of cancer development. Accumulated data reveals that plant compounds, particularly polyphenols, exert anti-cancer effects through acting on protein kinase signaling pathways. Many natural bioactives bind directly to oncogenic protein kinases and then alter their phosphorylation state, thus mitigating cell signaling pathways in carcinogenesis processes.
Challenges and limitations
Despite numerous advances, scientists are still trying to understand pathophysiology and application of kinase inhibitors for therapeutic benefit in clinical oncology. Kinase inhibition triggers a strong discerning pressure for cells to acquire resistance to chemotherapy through kinase mutations . Thus, the treatment and pathology of cancer are further complicated by the plethora of such mutations that occur in different kinases . There are two types of chemotherapy resistance: de novo resistance, which refers to the failure of an agent to produce any detectable response after initial treatment and acquired resistance. Multiple mechanisms including the targeted kinase, the structure of inhibitor, and the underlying genetic features of the tumor contribute to treatment failure and both types of resistance. Acquired resistance refers to the progression of a tumor that initially responds to treatment and subsequently becomes resistant to treatment despite continual administration of the inhibitor. Interestingly, most of the kinase resistant cases fall into the acquired resistant category. Treatment resistance associated with kinase inhibitors is induced by changes in the kinase gatekeeper residue as hydrophobic interactions on this site are crucial for the binding affinity of the inhibitor [265, 266]. Since a small gatekeeper residue allows an inhibitor to access the “gated” hydrophobic regions of the binding pocket, changes in this region hinder activity of kinase inhibitors. The gatekeeper residue has no interaction with ATP but is usually in contact with Type I and Type II kinase inhibitors and sterically impedes inhibitor binding . These mutations mainly lead to in the substitution of one amino acid for another in the protein made by a gene, thus conferring resistance to cell cycle termination and chemo drugs. A classic example is induction of imatinib resistance due to gatekeeper mutations in Thr 315 (coded by ACT) in BCR-ABL kinase . Other examples of such gatekeeper mutations include T790 (EGFR) , G697R (FLT3) , BCR–ABL1 (T315I) , PDGFRα (T674I)  and KIT (T670I)  oncogenic mutations. In the case of the EGFR kinase, the T790 M mutation induces resistance to quinazoline inhibitors by increasing affinity for the natural substrate ATP . It is one of the most common mutations in which methionine substitutes for threonine at amino acid position 790, conferring a growth advantage to cancer cells alongside drug-resistant variant of the targeted kinase . Similarly, 20% of cases of acquired TKI resistance involve amplification of the MET gene . These events thereby provide signalling redundancy and eliminate consequences of clinical kinase inactivation. Furthermore, the lipid modifying PI3K together with the Ras-Raf-MAPK also undergoes several resistance-inducing mutations . Interestingly, these mutations cause a minute or no change in kinase activity but confer inhibitor resistance to kinase inhibitors . An example includes gatekeeper mutation T790 M in EGFR which causes gefitinib and erlotinib resistance via hyper affinity for ATP [277, 278]. Overcoming gatekeeper-mutation induced drug-resistance in the clinic is extremely difficult and requires structural fine-tuning of the drug candidates. To surmount resistance to inhibitors gefitinib and erlotinib, kinase inhibitors that bind covalently to the ATP-binding site of EGFR are been developed [117, 279]. Such next-generation EGFR inhibitors selectively target the inhibitor-sensitizing mutations and display an improved safety profile by sparing wild-type EGFR activity in normal cells. A recent study using chemical proteomics analyzed 243 clinically evaluated kinase drugs and showed that some kinase inhibitors are highly selective, especially KIs targeting mutant EGFR . Likewise, G-loop mutations in ABL, p38α, FGFR1, CK2α1, JNK3, AURORA-A, ROCK1 and CDK5 kinases prompt oncogenic or drug-sensitizing mutations . Another clinical challenge associated with kinase inhibitors is variation in clinical results from combinations of kinase inhibitors. Examples of clinical failure include combined gefitinib and trastuzumab treatment in breast cancer, erlotinib and bevacizumab in renal cell carcinoma, and cetuximab and bevacizumab in colorectal cancer. Conversely, combinations of lapatinib and pertuzumab with trastuzumab in breast cancer, and combination of bevacizumab and erlotinib in NSCLC have exhibited clinical success. Further, in some cases, the combinations of kinase targeting agents reduced patient survival compared with the treatment using single drug . However, these discrepancies are proposed due to misinterpretation of the preclinical data, rather than a failure of the preclinical model itself [282, 283]. Additionally, these preclinical studies of drug combinations are probably biased towards validating well-characterized targets thereby limiting their ability to prioritize novel targets. Further, many kinase inhibitors are associated with toxicities and off-target effects such as cardiotoxicity, hypertension, hypothyroidism, skin reactions and proteinuria [284, 285]. Looking specifically, inhibition of EGFR is associated with dermatological problems, VEGFR inhibition with cardiotoxicity, HER2 and ALK inhibition with gastric irregularities and dermatological problems, and BCR-ABL inhibition causes cytopenia, in addition to cardiotoxicity and cardiac complications [286, 287]. Another challenge is in translating RNAi therapy into drugs, particularly in kinase inhibition. The majority of drug targets cannot be battered by shRNA (or gene knockout) as most shRNAs cannot be replicated by drugs since most proteins cannot be translated to therapy . Thus, clinical resistance to kinase inhibitors remains the major limitation to kinase-based -therapies. Resistance to chemotherapy has also been well recognized as a significant challenge in oncology, a problem also confronted by kinase inhibitors. Beyond the stated illustrative examples, numerous other pathways outside the scope of this review can influence the clinical activity of kinase inhibitors.
Numerous follow-up strategies are being employed to overcome the challenge of kinase inhibitor resistance. A first approach is to develop inhibitors that can tolerate diverse amino acids at the gatekeeper position [289, 290]. A second approach is to target the kinase with inhibitors that bind at alternative binding sites [115, 291]. A third approach involves targeting other pathways that may be required for kinase transformation . These approaches have been demonstrated to work in cell line studies, and strategies are being developed for their clinical use. However, it is also vital to consider the possibility that multiple different resistance mechanisms might develop concurrently in patients, thereby challenging clinical ability to overcome acquired resistance to kinase inhibitors.
Even though only a small fraction of the kinome is currently being targeted, kinase inhibitor drug discovery has progressed dramatically in the past decade. Clinical evaluation of kinase inhibitors has shown that therapeutic responses vary widely in individual patients and across patient populations, and seem to depend on many diverse factors. Many new candidate molecules have entered clinical trials, and much more are still at the preclinical stage. Most of the current kinase inhibitor discoveries have developed through rational drug design rather than through random screening and analysis of structure-activity relationships. An important strategy required for future development is to understand the basis of unexpected toxicities related to kinase inhibitors. Improvement in the documentation of toxicities of kinase inhibitor would provide a valuable database for understanding whether there are particular kinases of which inhibition should be avoided or specific substructures that result in problematic metabolites. This strategy will help to develop kinases with better selectivity benefitting the vast patient population. Also, there is a critical need for better ways to monitor target kinase inhibition in humans using minimally invasive techniques. This may include monitoring of cancer biomarkers that may serve as benchmarks for the clinical development of kinase inhibitors. The development of such technologies will help to discover and eradicate tumors using targeted kinase inhibition with minimal toxicities. There is also an urgent need for developing more non-ATP-competitive kinase inhibitors as the current collection of kinase inhibitors is limited to ABL, IKK, AKT, CHK1, MEK, SRC, IGF1R inhibitors [99, 293, 294, 295, 296]. Furthermore, there is need to develop sophisticated modeling of chemotherapy resistance in response to kinase inhibitors. This will help to overcome kinase resistance and allow for the systematic application of combinations of kinase inhibitors. Furthermore, novel pre-clinical models are required to identify the best cocktails of kinase inhibitors combined with natural bioactives. Advanced high-throughput cell-based screening using well-defined phosphorylation readouts should be established. However, it may prove challenging to screen and develop natural kinase inhibitors using the cellular readout only. It is also important to understand that kinase inhibitors are not only important for the treatment of cancer, but also help us better understand the physiological roles of kinases. In the field of oncology, kinase inhibitors are proving to be well tolerated compared with conventional cytotoxic chemotherapeutic treatments. The future of kinase-targeted therapeutics in cancer appears promising, and implementation of these strategies will help to achieve therapeutic advances and overcome treatment hindrances.
By transferring the γ-phosphate from the ATP-cofactor onto diverse substrates, kinases regulate key cellular functions. As many human diseases result from mutations and overexpression of kinases, this enzyme class symbolizes an important targeted strategy for drug development. Kinases also play indispensable roles in signaling pathways that regulate tumor cell functions. Deregulation of kinases leads to a variety of pathophysiological changes triggering cancer cell proliferation and metastases. Hyperactivation of kinases also increases anti-apoptotic effects. Currently, about one-third of all protein targets under research in the pharmaceutical industry are kinase-based. Kinase inhibitors represent targeted therapy resultant of the understanding of molecular genetics and molecular signaling pathways. Most of the FDA-approved kinase inhibitors target ATP binding site of kinase enzymes and display therapeutic indications against tumorigenesis. This class of therapeutics represents a transformation from conventional chemotherapy to targeted cancer treatment. Kinase inhibitors have overcome a major drawback of traditional cancer treatment as it effectively discriminates between normal non-malignant cells and rapidly proliferating cancer cells. This leads to fewer off-target effects and low toxicities in the cancer patient population. Kinase inhibitors are also often useful in combination with cytotoxic chemotherapy or radiation therapy. A vital challenge for clinical use of kinase inhibitors in the prevention of drug-resistant cancer stem cells. This phenomenon occurs due to cellular pressure to compensate for the loss of function of an important kinase. Pharmacogenomic factors including gene polymorphisms also contribute to primary kinase drug-resistance. Due to the clinical importance of kinase inhibitors, multiple strategies are required to overcome resistance mechanisms and develop more effective targeted therapies. A key approach is to allosterically induce and stabilize inactive kinase conformations. In the future, scientific advances may eventually allow scientists to combine mutagenesis screens through next generation sequencing and proteomic techniques with the computational modeling of compound interactions with all possible mutant variants of a targeted kinase. This will lead to the development of well-tolerated kinase inhibitors compared to traditional chemotherapeutic treatments. Overall, kinase inhibitors represent a new and promising approach to cancer therapy, one that is already providing beneficial clinical effects.
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