Mohedas Agustin H, Wang You, Sanvitale Caroline E, Canning Peter, Choi Sungwoon, Xing Xuechao, Bullock Alex N, Cuny Gregory D, Yu Paul B
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
J Med Chem. 2014 Oct 9;57(19):7900-15. doi: 10.1021/jm501177w. Epub 2014 Sep 4.
There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure-activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG.
进行性骨化性纤维发育不良（FOP）是一种由编码骨形态发生蛋白（BMP）I型受体激酶ALK2的ACVR1激活突变引起的使人衰弱的进行性异位骨化疾病，目前尚无有效的治疗方法。最近，在弥漫性脑桥内在胶质瘤（DIPG）肿瘤中发现了ACVR1的这些相同突变的一个子集。在此，我们描述了基于2-氨基吡啶化合物K02288的一系列新型ALK2抑制剂的构效关系。一些修饰提高了激酶、热迁移或基于细胞的BMP信号传导和转录测定中的效力，以及对ALK2相对于密切相关的BMP和TGF-βI型受体激酶的选择性。该系列化合物表现出广泛的体外细胞毒性，这与效力或选择性无关，提示其作用机制独立于BMP或TGF-β抑制。该研究还突出了一种有效的2-甲基吡啶衍生物10（LDN-214117），它对ALK2具有高度选择性且细胞毒性低，可为临床前开发提供模板。与ALK2激活突变可能由于ATP结合位点潜在的构象变化而改变抑制剂疗效的观点相反，这些化合物对一组突变型和野生型ALK2蛋白表现出一致的结合。因此，通过针对野生型ALK2信号传导的活性鉴定的BMP抑制剂可能与与FOP和DIPG相关的多种ALK2突变蛋白具有临床相关性。
