Skip to main content
SpringerLink
Log in

Target Engagement Measures in Preclinical Drug Discovery: Theory, Methods, and Case Studies

  • Chapter
  • First Online:
Translating Molecules into Medicines

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 25))

Abstract

Target engagement (TE) in drug discovery is generally defined as the interaction of ligands with their target biomolecules. Understanding TE allows research teams to design and interpret quality in vivo experiments, providing a more refined assessment of target validation. It can also orient teams toward delivering molecules that better enable clinical studies by focusing SAR efforts on the optimization of projected human performance characteristics. In this chapter, theoretical aspects of TE and its importance for addressing drug discovery issues like selectivity and the relationship of pharmacokinetics to pharmacodynamics are addressed. Methods to measure TE directly are reviewed along with a discussion of how to estimate TE based on pharmacokinetic data. The principles outlined within the chapter are then demonstrated by application to a theoretical drug discovery effort focused on validation of a novel protein target. Finally, two case studies are discussed in which application of these principles was used to optimize compounds toward desired human performance characteristics in one instance and to drive a target de-prioritization decision in another.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Durham TB, Blanco M-J. Target engagement in lead generation. Bioorg Med Chem Lett. 2015;25(5):998–1008.

    Article  PubMed  Google Scholar 

  2. Abou-Gharbia M, Childers WE. Discovery of innovative therapeutics: today’s realities and tomorrow’s vision. 2. Pharma’s challenges and their commitment to innovation. J Med Chem. 2014;57(13):5525–53.

    Article  CAS  PubMed  Google Scholar 

  3. Bunnage ME. Getting pharmaceutical R&D back on target. Nat Chem Biol. 2011;7(6):335–9.

    Article  CAS  PubMed  Google Scholar 

  4. Cook D, Brown D, Alexander R, et al. Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework. Nat Rev Drug Discov. 2014;13(6):419–31.

    Article  CAS  PubMed  Google Scholar 

  5. McGonigle P, Ruggeri B. Animal models of human disease: challenges in enabling translation. Biochem Pharmacol. 2014;87(1):162–71.

    Article  CAS  PubMed  Google Scholar 

  6. Morgan P, Van Der Graaf PH, Arrowsmith J, et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discov Today. 2012;17(9–10):419–24.

    Article  CAS  PubMed  Google Scholar 

  7. Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev Drug Discov. 2010;9(3):203–14.

    CAS  PubMed  Google Scholar 

  8. Tuntland T, Ethell B, Zang R, et al. Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at Novartis Institute of Biomedical Research. Front Pharmacol. 2014;5(174):1–16.

    CAS  Google Scholar 

  9. Wiley MR, Durham TB, Adams LA, et al. Use of osmotic pumps to establish the pharmacokinetic-pharmacodynamic relationship and define desirable human performance characteristics for aggrecanase inhibitors. J Med Chem. 2016;59(12):5810–22.

    Article  CAS  PubMed  Google Scholar 

  10. Hill AV. The possible effects of the aggregation of the molecules of hæmoglobin on its dissociation curves. J Physiol. 1910;40(Suppl):i–vii.

    Google Scholar 

  11. Dahlin JL, Nissink JWM, Strasser JM, et al. PAINS in the assay: chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS. J Med Chem. 2015;58(5):2091–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mariappan TT, Mandlekar S, Marathe P. Insight into tissue unbound concentration: utility in drug discovery and development. Curr Drug Metab. 2013;14(3):324–40.

    Article  CAS  PubMed  Google Scholar 

  13. Howard ML, Hill JJ, Galluppi GR, et al. Plasma protein binding in drug discovery and development. Comb Chem High Throughput Screen. 2010;13(2):170–87.

    Article  CAS  PubMed  Google Scholar 

  14. Lombardo F, Obach RS, Waters NJ. Plasma protein binding and volume of distribution: determination, prediction and use in early drug discovery. Methods Princ Med Chem. 2009;43(Hit and Lead Profiling):197–220.

    CAS  Google Scholar 

  15. Ramanathan V, Vachharajani N. Protein binding in drug discovery and development. In: Han C, Davis C, Wang B, editors. Evaluation of drug candidates for preclinical development: pharmacokinetics, metabolism, pharmaceutics, and toxicology. Hoboken, NJ: Wiley; 2010. p. 135–67.

    Google Scholar 

  16. Smith DA, Di L, Kerns EH. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov. 2010;9(12):929–39.

    Article  CAS  PubMed  Google Scholar 

  17. Trainor GL. The importance of plasma protein binding in drug discovery. Expert Opin Drug Discovery. 2007;2(1):51–64.

    Article  CAS  Google Scholar 

  18. Belpaire F. Species differences in protein binding. In: Van Miert ASJPAM, Bogaert MG, Debackere M, editors. Comparative veterinary pharmacology, toxicology and therapy. New York: Springer; 1986. p. 187–95.

    Chapter  Google Scholar 

  19. Bialer M, Tonelli AP, Kantrowitz JD, et al. Serum protein binding of a new oral cephalosporin, CL 284,635, in various species. Drug Metab Dispos. 1986;14(1):132–6.

    CAS  PubMed  Google Scholar 

  20. Lin JH. Species differences in protein binding of diflunisal. Drug Metab Dispos. 1989;17(2):221–3.

    CAS  PubMed  Google Scholar 

  21. Ito T, Takahashi M, Sudo K, et al. Marked strain differences in the pharmacokinetics of an α4β1 integrin antagonist, 4-[1-[3-chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic acid (D01-4582), in Sprague-Dawley rats are associated with albumin genetic polymorphism. J Pharmacol Exp Ther. 2007;320(1):124–32.

    Article  CAS  PubMed  Google Scholar 

  22. Piafsky KM, Borgå O, Odar-Cederlöf I, et al. Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma α1 acid glycoprotein. N Engl J Med. 1978;299(26):1435–9.

    Article  CAS  PubMed  Google Scholar 

  23. Abbott NJ. Blood-brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis. 2013;36(3):437–49.

    Article  CAS  PubMed  Google Scholar 

  24. Miller DS, Hawkins BT. Blood-brain barrier: considerations in drug development and delivery. In: Civjan N, editor. Chemical biology: approaches to drug discovery and development to targeting disease. Hoboken, NJ, USA: John Wiley & Sons, Inc.; 2012. p. 133–46.

    Chapter  Google Scholar 

  25. Bingham M, Rankovic Z. Medicinal chemistry challenges in CNS drug discovery. RSC Drug Discov Ser. 2012;28(Drug Discovery for Psychiatric Disorders):465–509.

    CAS  Google Scholar 

  26. Copeland RA. The dynamics of drug-target interactions: drug-target residence time and its impact on efficacy and safety. Expert Opin Drug Discovery. 2010;5(4):305–10.

    Article  CAS  Google Scholar 

  27. Copeland RA. Drug-target interactions: stay tuned. Nat Chem Biol. 2015;11(7):451–2.

    Article  CAS  PubMed  Google Scholar 

  28. Copeland RA. The drug-target residence time model: a 10-year retrospective. Nat Rev Drug Discov. 2016;15(2):87–95.

    Article  CAS  PubMed  Google Scholar 

  29. Copeland RA, Pompliano DL, Meek TD. Drug-target residence time and its implications for lead optimization. Nat Rev Drug Discov. 2006;5(9):730–9.

    Article  CAS  PubMed  Google Scholar 

  30. Adeniyi AA, Muthusamy R, Soliman MES. New drug design with covalent modifiers. Expert Opin Drug Discovery. 2016;11(1):79–90.

    Article  CAS  Google Scholar 

  31. Bauer RA. Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies. Drug Discov Today. 2015;20(9):1061–73.

    Article  CAS  PubMed  Google Scholar 

  32. Kalgutkar AS, Dalvie DK. Drug discovery for a new generation of covalent drugs. Expert Opin Drug Discovery. 2012;7(7):561–81.

    Article  CAS  Google Scholar 

  33. Singh J, Petter RC, Baillie TA, et al. The resurgence of covalent drugs. Nat Rev Drug Discov. 2011;10(4):307–17.

    Article  CAS  PubMed  Google Scholar 

  34. Copeland RA. Evaluation of enzyme inhibitors in drug discovery: a guide for medicinal chemists and pharmacologists. 2nd ed. Hoboken, NJ: John Wiley & Sons, Inc.; 2013.

    Book  Google Scholar 

  35. Triboulet S, Arthur M, Mainardi J-L, et al. Inactivation kinetics of a new target of β-lactam antibiotics. J Biol Chem. 2011;286(26):22777–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hayes A. Key role of publication of clinical data for target validation. Pharmacol Res Perspect. 2015;3(4):e00163.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hayes A, Hunter J. Why is publication of negative clinical trial data important? Br J Pharmacol. 2012;167(7):1395–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sweis RF. Target (in)validation: a critical, sometimes unheralded, role of modern medicinal chemistry. ACS Med Chem Lett. 2015;6(6):618–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Prinz F, Schlange T, Asadullah K. Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov. 2011;10(9):712.

    Article  CAS  PubMed  Google Scholar 

  40. Singh K, Walia MK, Agarwal G, et al. Osmotic pump drug delivery system: a novel approach. J Drug Deliv Ther. 2013;3(5):156–62.

    Google Scholar 

  41. Singla D, Hari Kumar SL, Nirmala G. Osmotic pump drug delivery—a novel approach. Int J Res Pharm Chem. 2012;2(3):661–70.

    CAS  Google Scholar 

  42. Theeuwes F, Yum SI. Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid drug formulations. Ann Biomed Eng. 1976;4(4):343–53.

    Article  CAS  PubMed  Google Scholar 

  43. Verma RK, Arora S, Garg S. Osmotic pumps in drug delivery. Crit Rev Ther Drug Carrier Syst. 2004;21(6):477–520.

    Article  CAS  PubMed  Google Scholar 

  44. Turner PV, Brabb T, Pekow C, et al. Administration of Substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci. 2011;50(5):600–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Almqvist H, Axelsson H, Jafari R, et al. CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil. Nat Commun. 2016;7:11040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jafari R, Almqvist H, Axelsson H, et al. The cellular thermal shift assay for evaluating drug target interactions in cells. Nat Protoc. 2014;9(9):2100–22.

    Article  CAS  PubMed  Google Scholar 

  47. Martinez Molina D, Nordlund P. The cellular thermal shift assay: a novel biophysical assay for in situ drug target engagement and mechanistic biomarker studies. Annu Rev Pharmacol Toxicol. 2016;56:141–61.

    Article  CAS  PubMed  Google Scholar 

  48. Molina DM, Jafari R, Ignatushchenko M, et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science. 2013;341(6141):84–7.

    Article  CAS  Google Scholar 

  49. Xu H, Gopalsamy A, Hett EC, et al. Cellular thermal shift and clickable chemical probe assays for the determination of drug-target engagement in live cells. Org Biomol Chem. 2016;14(26):6179–83.

    Article  CAS  PubMed  Google Scholar 

  50. Zhu B, Zhang H, Pan S, et al. In situ proteome profiling and bioimaging applications of small-molecule affinity-based probes derived from DOT1L inhibitors. Chem Eur J. 2016;22(23):7824–36.

    Article  CAS  PubMed  Google Scholar 

  51. Franken H, Mathieson T, Childs D, et al. Thermal proteome profiling for unbiased identification of direct and indirect drug targets using multiplexed quantitative mass spectrometry. Nat Protoc. 2015;10(10):1567–93.

    Article  CAS  PubMed  Google Scholar 

  52. Reinhard FBM, Eberhard D, Werner T, et al. Thermal proteome profiling monitors ligand interactions with cellular membrane proteins. Nat Methods. 2015;12(12):1129–31.

    Article  CAS  PubMed  Google Scholar 

  53. Savitski MM, Reinhard FBM, Franken H, et al. Tracking cancer drugs in living cells by thermal profiling of the proteome. Science. 2014a;346(6205):1255784.

    Article  PubMed  Google Scholar 

  54. Barth V, Need A. Identifying novel radiotracers for PET imaging of the brain: application of LC-MS/MS to tracer identification. ACS Chem Neurosci. 2014;5(12):1148–53.

    Article  CAS  PubMed  Google Scholar 

  55. Celen S, Koole M, Ooms M, et al. Preclinical evaluation of [18F]JNJ42259152 as a PET tracer for PDE10A. NeuroImage. 2013;82:13–22.

    Article  CAS  PubMed  Google Scholar 

  56. Chekol R, Gheysens O, Cleynhens J, et al. Evaluation of PET radioligands for in vivo visualization of phosphodiesterase 5 (PDE5). Nucl Med Biol. 2014;41(2):155–62.

    Article  CAS  PubMed  Google Scholar 

  57. Hargreaves RJ, Rabiner EA. Translational PET imaging research. Neurobiol Dis. 2014;61:32–8.

    Article  PubMed  Google Scholar 

  58. Nakatani Y, Suzuki M, Tokunaga M, et al. A small-animal pharmacokinetic/pharmacodynamic PET study of central serotonin 1A receptor occupancy by a potential therapeutic agent for overactive bladder. PLoS One. 2013;8(9):e75040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Plisson C, Weinzimmer D, Jakobsen S, et al. Phosphodiesterase 10A PET radioligand development program: from pig to human. J Nucl Med. 2014;55(4):595–601.

    Article  CAS  PubMed  Google Scholar 

  60. Schroeder FA, Wang C, Van de Bittner GC, et al. PET imaging demonstrates histone deacetylase target engagement and clarifies brain penetrance of known and novel small molecule inhibitors in rat. ACS Chem Neurosci. 2014;5(10):1055–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tu Z, Fan J, Li S, et al. Radiosynthesis and in vivo evaluation of [11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain. Bioorg Med Chem. 2011;19(5):1666–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhang L, Villalobos A, Beck EM, et al. Design and selection parameters to accelerate the discovery of novel central nervous system positron emission tomography (PET) ligands and their application in the development of a novel phosphodiesterase 2A PET ligand. J Med Chem. 2013;56(11):4568–79.

    Article  CAS  PubMed  Google Scholar 

  63. Barth VN, Chernet E, Martin LJ, et al. Comparison of rat dopamine D2 receptor occupancy for a series of antipsychotic drugs measured using radiolabeled or nonlabeled raclopride tracer. Life Sci. 2006;78(26):3007–12.

    Article  CAS  PubMed  Google Scholar 

  64. Barth VN, Joshi EM, Silva MD. Target engagement for PK/PD modeling and translational imaging biomarkers. In: Zhang D, Surapaneni S, editors. ADME-enabling technologies in drug design and development. Hoboken, NJ: John Wiley & Sons, Inc.; 2012. p. 493–511.

    Chapter  Google Scholar 

  65. Hu E, Ma J, Biorn C, et al. Rapid identification of a novel small molecule phosphodiesterase 10A (PDE10A) tracer. J Med Chem. 2012;55(10):4776–87.

    Article  CAS  PubMed  Google Scholar 

  66. Evans EK, Tester R, Aslanian S, et al. Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J Pharmacol Exp Ther. 2013;346(2):219–28.

    Article  CAS  PubMed  Google Scholar 

  67. Ahmed T, Rohatagi S. Application of LC-MS in supporting PK/PD studies during drug discovery and development. J Pharm Res. 2012;5(5):2514–26.

    CAS  Google Scholar 

  68. Mei H, Morrison RA. PK principles and PK/PD applicatons. In: Korfmacher WA, editor. Using mass spectrometry for drug metabolism studies. 2nd ed. Boca Raton, FL: CRC Press; 2009. p. 59–98.

    Chapter  Google Scholar 

  69. Szekely-Klepser G, Kindt E. The role of biomarkers in drug discovery and development: enabling PK/PD encyclopedia of drug metabolism and interactions. Hoboken, NJ: John Wiley & Sons, Inc.; 2012. p. 1–22.

    Google Scholar 

  70. Durham TB, Toth JL, Klimkowski VJ, et al. Dual exosite-binding inhibitors of insulin-degrading enzyme challenge its role as the primary mediator of insulin clearance in vivo. J Biol Chem. 2015;290(33):20044–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Malito E, Hulse RE, Tang WJ. Amyloid β-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin. Cell Mol Life Sci. 2008;65(16):2574–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bennett RG, Duckworth WC, Hamel FG. Degradation of amylin by insulin-degrading enzyme. J Biol Chem. 2000;275(47):36621–5.

    Article  CAS  PubMed  Google Scholar 

  73. Chesneau V, Rosner MR. Functional human insulin-degrading enzyme can Be expressed in bacteria. Protein Expr Purif. 2000;19(1):91–8.

    Article  CAS  PubMed  Google Scholar 

  74. Guo Q, Manolopoulou M, Bian Y, et al. Molecular basis for the recognition and cleavages of IGF-II, TGF-α, and amylin by human insulin-degrading enzyme. J Mol Biol. 2010;395(2):430–43.

    Article  CAS  PubMed  Google Scholar 

  75. Im H, Manolopoulou M, Malito E, et al. Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J Biol Chem. 2007;282(35):25453–63.

    Article  CAS  PubMed  Google Scholar 

  76. Mullard A. Reliability of ‘new drug target’ claims called into question. Nat Rev Drug Discov. 2011;10(9):643–4.

    Article  CAS  PubMed  Google Scholar 

  77. Ralat LA, Guo Q, Ren M, et al. Insulin-degrading enzyme modulates the natriuretic peptide-mediated signaling response. J Biol Chem. 2011a;286(6):4670–9.

    Article  CAS  PubMed  Google Scholar 

  78. Ralat LA, Kalas V, Zheng Z-Z, et al. Ubiquitin is a novel substrate for human insulin-degrading enzyme. J Mol Biol. 2011b;406(3):454–66.

    Article  CAS  PubMed  Google Scholar 

  79. Tundo GR, Sbardella D, Ciaccio C, et al. Insulin-degrading enzyme (IDE): a novel heat shock-like protein. J Biol Chem. 2013;288(4):2281–9.

    Article  CAS  PubMed  Google Scholar 

  80. Abdul-Hay SO, Kang D, McBride M, et al. Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. PLoS One. 2011;6(6):e20818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100(7):4162–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Steneberg P, Bernardo L, Edfalk S, et al. The type 2 diabetes-associated gene Ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Diabetes. 2013;62(6):2004–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bennett RG, Hamel FG, Duckworth WC. An insulin-degrading enzyme inhibitor decreases amylin degradation, increases amylin-induced cytotoxicity, and increases amyloid formation in insulinoma cell cultures. Diabetes. 2003;52(9):2315–20.

    Article  CAS  PubMed  Google Scholar 

  84. Durham TB, Klimkowski VJ, Rito CJ, et al. Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis. J Med Chem. 2014;57(24):10476–85.

    Article  CAS  PubMed  Google Scholar 

  85. Simkin PA, Pizzorno JE. Transynovial exchange of small molecules in normal human subjects. J Appl Physiol. 1974;36(5):581–7.

    CAS  PubMed  Google Scholar 

  86. Glasson SS, Askew R, Sheppard B, et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature. 2005;434(7033):644–8.

    Article  CAS  PubMed  Google Scholar 

  87. Glasson SS, Askew R, Sheppard B, et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum. 2004;50(8):2547–58.

    Article  CAS  PubMed  Google Scholar 

  88. Malfait A-M, Tortorella M, Arner E. ADAMTS-4 and ADAMTS-5: aggrecanases. Proteases Biol Dis. 2005;4(ADAM Family of Proteases):299–322.

    Article  CAS  Google Scholar 

  89. Song R-H, Tortorella MD, Malfait A-M, et al. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum. 2007;56(2):575–85.

    Article  CAS  PubMed  Google Scholar 

  90. Tortorella MD, Malfait F, Barve RA, et al. A review of the ADAMTS family, pharmaceutical targets of the future. Curr Pharm Des. 2009;15(20):2359–74.

    Article  CAS  PubMed  Google Scholar 

  91. Verma P, Dalal K. ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem. 2011;112(12):3507–14.

    Article  CAS  PubMed  Google Scholar 

  92. Li J, Anemaet W, Diaz MA, et al. Knockout of ADAMTS5 does not eliminate cartilage aggrecanase activity but abrogates joint fibrosis and promotes cartilage aggrecan deposition in murine osteoarthritis models. J Orthop Res. 2011;29(4):516–22.

    Article  CAS  PubMed  Google Scholar 

  93. Little CB, Meeker CT, Golub SB, et al. Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair. J Clin Invest. 2007;117(6):1627–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Majumdar MK, Askew R, Schelling S, et al. Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis. Arthritis Rheum. 2007;56(11):3670–4.

    Article  CAS  PubMed  Google Scholar 

  95. Stanton H, Rogerson FM, East CJ, et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature. 2005;434(7033):648–52.

    Article  CAS  PubMed  Google Scholar 

  96. Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci. 2006;11(2):1696–701.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Timothy B. Durham & Michael R. Wiley

Authors
  1. Timothy B. Durham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael R. Wiley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Timothy B. Durham .

Editor information

Editors and Affiliations

  1. Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana, USA

    Shobha N. Bhattachar

  2. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Wallingford, Connecticut, USA

    John S. Morrison

  3. ADME, Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana, USA

    Daniel R. Mudra

  4. Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana, USA

    David M. Bender

Rights and permissions

Reprints and permissions

Copyright information

© 2017 American Association of Pharmaceutical Scientists

About this chapter

Cite this chapter

Durham, T.B., Wiley, M.R. (2017). Target Engagement Measures in Preclinical Drug Discovery: Theory, Methods, and Case Studies. In: Bhattachar, S., Morrison, J., Mudra, D., Bender, D. (eds) Translating Molecules into Medicines. AAPS Advances in the Pharmaceutical Sciences Series, vol 25. Springer, Cham. https://doi.org/10.1007/978-3-319-50042-3_3

Download citation

Publish with us

Policies and ethics

Search

Navigation