DDR-TRK-1

DDR-TRK-1 is an inhibitor of discoidin domain receptor 1 (DDR1; IC₅₀ = 9.4 nM).¹ It is selective for DDR1 over DDR2 and Abl1 (IC₅₀s = 188 and >10,000 nM, respectively) and 461 additional kinases at 1 µM but does inhibit cyclin-dependent kinase 11 (Cdk11), ephrin type-A receptor 8 (EPHA8), muscle-associated receptor tyrosine kinase (MUSK), tropomyosin-related kinase A (TrkA), TrkB, and TrkC at 1 µM. However, DDR-TRK-1 selectively binds to DDR1 (K_d = 4.7 nM) over Cdk11, EPHA8, MUSK, and TrkA (K_ds = 370, 550, 530, and 100 nM, respectively) but does bind to TrkB and TrkC (K_ds = 22 and 18 nM, respectively). It reduces the levels of phosphorylated DDR1 and phosphorylated p38 MAPK, which is downstream of DDR1, in primary human lung fibroblasts when used at concentrations ranging from 0.25 to 1 µM. DDR-TRK-1 (10 and 50 mg/kg twice per day) reduces pulmonary fibrosis induced by the profibrotic glycopeptide antitumor antibiotic bleomycin (Item No. 13877) in mice.

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1. Wang, Z., Bian, H., Bartual, S.G., et al. Structure-based design of tetrahydroisoquinoline-7-carboxamides as selective discoidin domain receptor 1 (DDR1) inhibitors. J. Med. Chem. 59(12), 5911-5916 (2016).