Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, Room 4207, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
J Med Chem. 2020 May 14;63(9):4978-4996. doi: 10.1021/acs.jmedchem.0c00395. Epub 2020 May 5.
Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of , an analogue of the previously reported ALK2 inhibitor . Although highly selective for ALK2 over the TGF-βR1 receptor ALK5, is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.
弥漫性内在脑桥神经胶质瘤是一种侵袭性儿童癌症，目前尚无有效的化疗药物。对这种疾病的基因组景观分析导致鉴定出丝氨酸/苏氨酸激酶 ALK2 作为治疗干预的潜在靶标。在这项工作中，我们采用开放科学的方法来开发一系列有效的 I 型 ALK2 抑制剂，这些抑制剂具有口服生物利用度和脑穿透性。最初的努力导致发现了 ，这是先前报道的 ALK2 抑制剂 的类似物。尽管 对 TGF-βR1 受体 ALK5 具有高度选择性，但它对 hERG 钾通道也具有适度的活性。改变三甲氧基苯基部分的取代基产生了等效力的苯甲酰胺类似物 ，其对离子通道的非靶标亲和力降低。进一步的修饰得到了 2-氟-6-甲氧基苯甲酰胺衍生物 ()，它们对 ALK2 具有高抑制活性、优异的选择性和优越的药代动力学特性。
