A New Class of Small Molecule Inhibitor of BMP Signaling

Abstract

Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.

Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance

“…Gremlin 1 is thought to have various effects on non-BMP signaling (41). we performed the same experiments using LDN-193189 [a small molecule inhibitor of BMP type I receptors ALk2 and ALk3 (42)(43)(44)] to confirm that our obtained results of Gremlin 1 were via BMP signaling. Exposure of CaSki cells to LDN-193189 increased the expression of Nanog mRNA in a dose-dependent manner and significantly high expression of Nanog mRNA was observed compared to the vehicle control when the concentration of LDN-193189 was 100 nM (data not shown).…”

SMAD signaling and redox imbalance cooperate to induce prostate cancer cell dormancy

“…40 Recombinant human Activin A was from R&D systems (Catalog No 338-AC, lot BNV3211101). K-02288 41 Technologies). Cloning efficiency assays were mostly performed in 6 cm-diameter dishes seeded with 10 3 to 4 £ 10 3 cells.…”

Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva

“…The vast majority of drug candidates for FOP treatment suppress the abnormal activation of BMP signaling. Examples include direct kinase inhibitors of the catalytic domain of BMP type I receptors, such as dorsomorphin, LDN-193189, DMH1, RK-0071142, ML357, LDN-212854, and K0288, which consequently suppress the phosphorylation of the downstream effectors SMAD1/5/8 (22)(23)(24)(25)(26)(27); RARγ agonists, which reduce the expression of SMAD1/5/8 by protein degradation (28); allele-specific RNAi (ASP-RNAi) that target mutated ACVR1 (FOP-ACVR1) mRNA for degradation (29,30); inhibitors of hypoxiainducible factor-1α (HIF1α), which prevent the formation of mesenchymal condensations (31) or amplification of BMP signaling (32); and others (33,34). Among these drug candidates, only palovarotene (28,(35)(36)(37), a RARγ agonist, is now in clinical trial.…”