Skip to main content
SpringerLink
Log in

Novel potent and highly selective DDR1 inhibitors from integrated lead finding

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase and an attractive anti-fibrotic target. To identify novel DDR1 inhibitors, we used an integrated lead-finding approach relying in parallel on structure-based hybrid design and a focused screening campaign. Combining structural elements from both approaches allowed us to quickly overcome several compound liabilities and optimize the hits to advanced lead compounds. Despite a very high sequence conservation between DDR1 and DDR2, we were able to identify potent DDR1 inhibitors with close to 1000-fold selectivity against DDR2 as well as good selectivity against the full kinome. Exploitation of a DDR1 selectivity pocket detected by structural bioinformatics was crucial in the optimization process. Compounds with very high selectivity suffered from poor metabolic stability in rodents but may serve as useful DDR1-selective in vitro tool molecules.

Graphical Abstract

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Scheme 1
Scheme 2
Scheme 3

Similar content being viewed by others

Abbreviations

ADMET:

Absorption-Distribution-Metabolism-Excretion-Toxicity

ATP:

Adenosine 5′-Triphosphate

CSD:

Cambridge Structural Database

DDR1:

Discoidin Domain Receptor 1

GSH:

Glutathione

GST:

Glutathione D-transferase

RTK:

Receptor Tyrosine Kinase

SAR:

Structure–Activity Relationship

SF:

Selectivity Factor

References

  1. Leitinger B. Discoidin domain receptor functions in physiological and pathological conditions. In: Jeon KW, editor. International review of cell and molecular biology. Academic Press; 2014. p. 39–87. https://doi.org/10.1016/B978-0-12-800180-6.00002-5

  2. Moll S, Desmoulière A, Moeller MJ, Pache JC, Badi L, Arcadu F, et al. DDR1 role in fibrosis and its pharmacological targeting. Biochim Biophys Acta Mol Cell Res. 2019;1866:118474 https://doi.org/10.1016/j.bbamcr.2019.04.004

    Article  CAS  PubMed  Google Scholar 

  3. Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997;1:13–23. https://doi.org/10.1016/s1097-2765(00)80003-9

    Article  CAS  PubMed  Google Scholar 

  4. Yeh YC, Lin HH, Tang MJ. A tale of two collagen receptors, integrin β1 and discoidin domain receptor 1, in epithelial cell differentiation. Am J Physiol-Cell Physiol. 2012;303:C1207–17. https://doi.org/10.1152/ajpcell.00253.2012

    Article  CAS  PubMed  Google Scholar 

  5. Borza CM, Pozzi A. Discoidin domain receptors in disease. Matrix Biol. 2014;34:185–92. https://doi.org/10.1016/j.matbio.2013.12.002

    Article  CAS  PubMed  Google Scholar 

  6. Moll S, Yasui Y, Abed A, Murata T, Shimada H, Maeda A, et al. Selective pharmacological inhibition of DDR1 prevents experimentally-induced glomerulonephritis in prevention and therapeutic regime. J Transl Med. 2018;16:148 https://doi.org/10.1186/s12967-018-1524-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rammal H, Saby C, Magnien K, Van-Gulick L, Garnotel R, Buache E, et al. Discoidin domain receptors: potential actors and targets in cancer. Front Pharmacol. 2016;7:55 https://doi.org/10.3389/fphar.2016.00055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li Y, Lu X, Ren X, Ding K. Small molecule discoidin domain receptor kinase inhibitors and potential medical applications. J Med Chem. 2015;58:3287–301. https://doi.org/10.1021/jm5012319

    Article  CAS  PubMed  Google Scholar 

  9. Denny WA, Flanagan JU. Inhibitors of discoidin domain receptor (DDR) kinases for cancer and inflammation. Biomolecules. 2021;11:1671 https://doi.org/10.3390/biom11111671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Day E, Waters B, Spiegel K, Alnadaf T, Manley PW, Buchdunger E, et al. Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. Eur J Pharmacol. 2008;599:44–53. https://doi.org/10.1016/j.ejphar.2008.10.014

    Article  CAS  PubMed  Google Scholar 

  11. Kim HG, Tan L, Weisberg EL, Liu F, Canning P, Choi HG, et al. Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. ACS Chem Biol. 2013;8:2145–50. https://doi.org/10.1021/cb400430t

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu L, Hussain M, Luo J, Duan A, Chen C, Tu Z, et al. Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors. Chem Biol Drug Des. 2017;89:420–7. https://doi.org/10.1111/cbdd.12863

    Article  CAS  PubMed  Google Scholar 

  13. Wang Z, Bian H, Bartual SG, Du W, Luo J, Zhao H, et al. Structure-based design of tetrahydroisoquinoline-7-carboxamides as selective discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem. 2016;59:5911–6. https://doi.org/10.1021/acs.jmedchem.6b00140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang Z, Zhang Y, Bartual SG, Luo J, Xu T, Du W, et al. Tetrahydroisoquinoline-7-carboxamide derivatives as new selective discoidin domain receptor 1 (DDR1) inhibitors. ACS Med Chem Lett. 2017;8:327–32. https://doi.org/10.1021/acsmedchemlett.6b00497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhu D, Huang H, Pinkas DM, Luo J, Ganguly D, Fox AE, et al. 2-Amino-2,3-dihydro-1H-indene-5-carboxamide-based discoidin domain receptor 1 (DDR1) inhibitors: design, synthesis, and in vivo antipancreatic cancer efficacy. J Med Chem. 2019;62:7431–44. https://doi.org/10.1021/acs.jmedchem.9b00365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gao M, Duan L, Luo J, Zhang L, Lu X, Zhang Y, et al. Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem. 2013;56:3281–95. https://doi.org/10.1021/jm301824k

    Article  CAS  PubMed  Google Scholar 

  17. Wang Z, Zhang Y, Pinkas DM, Fox AE, Luo J, Huang H, et al. Design, synthesis, and biological evaluation of 3-(Imidazo[1,2-a]pyrazin-3-ylethynyl)-4-isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a dual inhibitor of discoidin domain receptors 1 and 2. J Med Chem. 2018;61:7977–90. https://doi.org/10.1021/acs.jmedchem.8b01045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mo C, Zhang Z, Li Y, Huang M, Zou J, Luo J, et al. Design and optimization of 3′-(Imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors. ACS Med Chem Lett. 2020;11:379–84. https://doi.org/10.1021/acsmedchemlett.9b00495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Murray CW, Berdini V, Buck IM, Carr ME, Cleasby A, Coyle JE, et al. Fragment-based discovery of potent and selective DDR1/2 inhibitors. ACS Med Chem Lett. 2015;6:798–803. https://doi.org/10.1021/acsmedchemlett.5b00143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Richter H, Satz AL, Bedoucha M, Buettelmann B, Petersen AC, Harmeier A, et al. DNA-encoded library-derived DDR1 inhibitor prevents fibrosis and renal function loss in a genetic mouse model of alport syndrome. ACS Chem Biol. 2019;14:37–49. https://doi.org/10.1021/acschembio.8b00866

    Article  CAS  PubMed  Google Scholar 

  21. Zhavoronkov A, Ivanenkov YA, Aliper A, Veselov MS, Aladinskiy VA, Aladinskaya AV, et al. Deep learning enables rapid identification of potent DDR1 kinase inhibitors. Nat Biotechnol. 2019;37:1038–40. https://doi.org/10.1038/s41587-019-0224-x

    Article  CAS  PubMed  Google Scholar 

  22. Yoshimori A, Asawa Y, Kawasaki E, Tasaka T, Matsuda S, Sekikawa T, et al. Design and synthesis of DDR1 inhibitors with a desired pharmacophore using deep generative models. ChemMedChem. 2021;16:955–8. https://doi.org/10.1002/cmdc.202000786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tan X, Li C, Yang R, Zhao S, Li F, Li X, et al. Discovery of pyrazolo[3,4-d]pyridazinone derivatives as selective ddr1 inhibitors via deep learning based design, synthesis, and biological evaluation. J Med Chem. 2022;65:103–19. https://doi.org/10.1021/acs.jmedchem.1c01205

    Article  CAS  PubMed  Google Scholar 

  24. Murata T, Niizuma S, Hara S, Kawada H, Hada K, Shimada H, et al. Benzamide derivative. WO2013161851, 2013.

  25. Hanson SM, Georghiou G, Thakur MK, Miller WT, Rest JS, Chodera JD. et al. What makes a kinase promiscuous for inhibitors?. Cell Chem Biol.2019;26:390–399. https://doi.org/10.1016/j.chembiol.2018.11.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol. 2006;2:358–64. https://doi.org/10.1038/nchembio799

    Article  CAS  PubMed  Google Scholar 

  27. Jeffries DE, Borza CM, Blobaum AL, Pozzi A, Lindsley CW. Discovery of VU6015929: a selective discoidin domain receptor 1/2 (DDR1/2) inhibitor to explore the role of DDR1 in antifibrotic therapy. ACS Med Chem Lett. 2020;11:29–33. https://doi.org/10.1021/acsmedchemlett.9b00382

    Article  CAS  PubMed  Google Scholar 

  28. Maass P, Schulz-Gasch T, Stahl M, Rarey M. Recore: a fast and versatile method for scaffold hopping based on small molecule crystal structure conformations. J Chem Inf Model. 2007;47:390–9. https://doi.org/10.1021/ci060094h

    Article  CAS  PubMed  Google Scholar 

  29. Kuhn B, Fuchs JE, Reutlinger M, Stahl M, Taylor NR. Rationalizing tight ligand binding through cooperative interaction networks. J Chem Inf Model. 2011;51:3180–98. https://doi.org/10.1021/ci200319e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shishkov IF, Khristenko LV, Vilkov LV, Oberhammer H. Structure and conformation of 4-fluoro(trifluoromethoxy)benzene: gas electron diffraction and quantum chemical calculations. J Phys Chem A. 2004;108:4966–70. https://doi.org/10.1021/jp0492671

    Article  CAS  Google Scholar 

  31. Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005;23:329–36. https://doi.org/10.1038/nbt1068

    Article  CAS  PubMed  Google Scholar 

  32. Hou G, Vogel W, Bendeck MP. The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. J Clin Investig. 2001;107:727–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Labrador JP, Azcoitia V, Tuckermann J, Lin C, Olaso E, Mañes S, et al. The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep. 2001;2:446–52. https://doi.org/10.1093/embo-reports/kve094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Honold K, Schaefer W, Scheiblich S. Heteroaryl derivatives as protein kinase inhibitors. WO2008028617, 2008.

  35. Rogers D, Hahn M. Extended-connectivity fingerprints. J Chem Inf Model. 2010;50:742–54. https://doi.org/10.1021/ci100050t

    Article  CAS  PubMed  Google Scholar 

  36. Stahl M, Mauser H, Tsui M, Taylor NR. A robust clustering method for chemical structures. J Med Chem. 2005;48:4358–66. https://doi.org/10.1021/jm040213p

    Article  CAS  PubMed  Google Scholar 

  37. Hawkins PCD, Skillman AG, Nicholls A. Comparison of shape-matching and docking as virtual screening tools. J Med Chem. 2007;50:74–82. https://doi.org/10.1021/jm0603365

    Article  CAS  PubMed  Google Scholar 

  38. Canning P, Tan L, Chu K, Lee SW, Gray NS, Bullock AN. Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors. J Mol Biol. 2014;426:2457–70. https://doi.org/10.1016/j.jmb.2014.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol. 1997;267:727–48. https://doi.org/10.1006/jmbi.1996.0897

    Article  CAS  PubMed  Google Scholar 

  40. Kabsch W. XDS. Acta Crystallogr D Biol Crystallogr. 2010;66:125–32. https://doi.org/10.1107/S0907444909047337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010;66:486–501. https://doi.org/10.1107/S0907444910007493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liebschner D, Afonine PV, Baker ML, Bunkóczi G, Chen VB, Croll TI, et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr D Struct Biol. 2019;75:861–77. https://doi.org/10.1107/S2059798319011471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge K. Hasegawa for DDR1 construct design. KH is an employee of Chugai Pharmaceutical Co. Ltd. We are also grateful to T. Bülau, B. Gsell, and D. Schlatter for DDR1-related protein activities and M. Bürkler for analytical measurements. TB, BG, DS, and MB are employees of Hoffmann-La Roche Ltd.

Author information

Authors and Affiliations

  1. Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland

    Bernd Kuhn, Martin Ritter, Jörg Benz, Buelent Kocer, Jérôme C. Sarie, Remo Hochstrasser, Markus G. Rudolph, Hans Richter & Marco Prunotto

  2. Research Division, Chugai Pharmaceutical Co. Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan

    Shojiro Kadono, Tetsu Matsuura & Takeshi Murata

  3. School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland

    Marco Prunotto

Authors
  1. Bernd Kuhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Ritter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jörg Benz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Buelent Kocer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jérôme C. Sarie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Remo Hochstrasser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Markus G. Rudolph
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shojiro Kadono
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tetsu Matsuura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takeshi Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hans Richter
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marco Prunotto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernd Kuhn.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Dedicated to Dr. Nick Meanwell for his numerous outstanding contributions to the field of molecular recognition.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kuhn, B., Ritter, M., Benz, J. et al. Novel potent and highly selective DDR1 inhibitors from integrated lead finding. Med Chem Res 32, 1400–1425 (2023). https://doi.org/10.1007/s00044-023-03066-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-023-03066-2

Keywords

Search

Navigation