Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.
PLoS One. 2013 Apr 30;8(4):e62721. doi: 10.1371/journal.pone.0062721. Print 2013.
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.
生长因子信号通路受磷酸化的严格调控，包括许多药物发现中感兴趣的重要激酶靶标。迫切需要骨形态发生蛋白（BMP）受体激酶 ALK2（ACVR1）的小分子抑制剂来治疗进行性衰弱的肌肉骨骼疾病纤维发育不良性骨化症（FOP）。在斑马鱼中首次鉴定出的 Dorsomorphin 类似物仍然是迄今为止报道的唯一 BMP 抑制剂化学型。通过筛选 250 种重组人激酶的测定试剂盒，我们鉴定出一种高选择性的 2-氨基吡啶基抑制剂 K02288，其对 ALK2 的体外活性在低纳摩尔浓度下类似于目前的先导化合物 LDN-193189。K02288 特异性抑制 BMP 诱导的 Smad 通路，而不影响 TGF-β信号通路，并诱导斑马鱼胚胎的背侧化。ALK2 与 K02288 和 LDN-193189 的晶体结构比较揭示了 K02288 复合物中的其他接触点，从而提供了更好的形状互补性，并确定了暴露的酚基以进一步优化药代动力学。新化学系列的发现为研究 BMP 信号提供了一种独立的药理学工具，并为临床前开发提供了多种机会。
