| Structural highlights
Disease
[DDR2_HUMAN] Defects in DDR2 are the cause of spondyloepimetaphyseal dysplasia short limb-hand type (SEMD-SL) [MIM:271665]. A bone disease characterized by short-limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping.[1] [2]
Function
[DDR2_HUMAN] Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing.[3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
The importance of DDR1 in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivo model have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitro safety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45 modulates DDR1 phosphorylation in vitro as well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45 preserves renal function and reduces tissue damage in Col4a3-/- mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3-/- mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population.
DNA-encoded library-derived DDR1 inhibitor prevents fibrosis and renal function loss in a genetic mouse model of Alport syndrome.,Richter H, Satz AL, Bedoucha M, Buettelmann B, Petersen AC, Harmeier A, Hermosilla R, Hochstrasser R, Burger D, Gsell B, Gasser R, Huber S, Hug MN, Kocer B, Kuhn B, Ritter M, Rudolph MG, Weibel F, Molina-David J, Kim JJ, Santos JV, Stihle M, Georges GJ, Bonfil RD, Fridman R, Uhles S, Moll S, Faul C, Fornoni A, Prunotto M ACS Chem Biol. 2018 Nov 19. doi: 10.1021/acschembio.8b00866. PMID:30452219[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ali BR, Xu H, Akawi NA, John A, Karuvantevida NS, Langer R, Al-Gazali L, Leitinger B. Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients. Hum Mol Genet. 2010 Jun 1;19(11):2239-50. doi: 10.1093/hmg/ddq103. Epub 2010 Mar , 10. PMID:20223752 doi:10.1093/hmg/ddq103
- ↑ Bargal R, Cormier-Daire V, Ben-Neriah Z, Le Merrer M, Sosna J, Melki J, Zangen DH, Smithson SF, Borochowitz Z, Belostotsky R, Raas-Rothschild A. Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications. Am J Hum Genet. 2009 Jan;84(1):80-4. doi: 10.1016/j.ajhg.2008.12.004. Epub 2008, Dec 24. PMID:19110212 doi:10.1016/j.ajhg.2008.12.004
- ↑ Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997 Dec;1(1):13-23. PMID:9659899
- ↑ Yang K, Kim JH, Kim HJ, Park IS, Kim IY, Yang BS. Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation. J Biol Chem. 2005 Nov 25;280(47):39058-66. Epub 2005 Sep 26. PMID:16186108 doi:10.1074/jbc.M506921200
- ↑ Wall SJ, Werner E, Werb Z, DeClerck YA. Discoidin domain receptor 2 mediates tumor cell cycle arrest induced by fibrillar collagen. J Biol Chem. 2005 Dec 2;280(48):40187-94. Epub 2005 Sep 26. PMID:16186104 doi:10.1074/jbc.M508226200
- ↑ Xu L, Peng H, Glasson S, Lee PL, Hu K, Ijiri K, Olsen BR, Goldring MB, Li Y. Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis. Arthritis Rheum. 2007 Aug;56(8):2663-73. PMID:17665456 doi:10.1002/art.22761
- ↑ Konitsiotis AD, Raynal N, Bihan D, Hohenester E, Farndale RW, Leitinger B. Characterization of high affinity binding motifs for the discoidin domain receptor DDR2 in collagen. J Biol Chem. 2008 Mar 14;283(11):6861-8. Epub 2008 Jan 16. PMID:18201965 doi:10.1074/jbc.M709290200
- ↑ Lin KL, Chou CH, Hsieh SC, Hwa SY, Lee MT, Wang FF. Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation. J Bone Miner Res. 2010 Nov;25(11):2489-503. doi: 10.1002/jbmr.159. PMID:20564243 doi:10.1002/jbmr.159
- ↑ Zhang Y, Su J, Yu J, Bu X, Ren T, Liu X, Yao L. An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation. J Bone Miner Res. 2011 Mar;26(3):604-17. doi: 10.1002/jbmr.225. PMID:20734453 doi:10.1002/jbmr.225
- ↑ Carafoli F, Bihan D, Stathopoulos S, Konitsiotis AD, Kvansakul M, Farndale RW, Leitinger B, Hohenester E. Crystallographic insight into collagen recognition by discoidin domain receptor 2. Structure. 2009 Dec 9;17(12):1573-81. PMID:20004161 doi:10.1016/j.str.2009.10.012
- ↑ Richter H, Satz AL, Bedoucha M, Buettelmann B, Petersen AC, Harmeier A, Hermosilla R, Hochstrasser R, Burger D, Gsell B, Gasser R, Huber S, Hug MN, Kocer B, Kuhn B, Ritter M, Rudolph MG, Weibel F, Molina-David J, Kim JJ, Santos JV, Stihle M, Georges GJ, Bonfil RD, Fridman R, Uhles S, Moll S, Faul C, Fornoni A, Prunotto M. DNA-encoded library-derived DDR1 inhibitor prevents fibrosis and renal function loss in a genetic mouse model of Alport syndrome. ACS Chem Biol. 2018 Nov 19. doi: 10.1021/acschembio.8b00866. PMID:30452219 doi:http://dx.doi.org/10.1021/acschembio.8b00866
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