Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
J Med Chem. 2020 Sep 10;63(17):10061-10085. doi: 10.1021/acs.jmedchem.0c01199. Epub 2020 Aug 26.
There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound . Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds , , and , each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.
目前尚无有效的化疗药物被批准用于治疗弥漫性内在脑桥神经胶质瘤（DIPG），这是一种侵袭性儿童脑癌，位于脑干的脑桥区域。放射治疗是有益的，但不能治愈，这种疾病的死亡率是一致的。对 DIPG 周围基因组景观的分析表明，激活素受体样激酶-2（ALK2）构成了治疗干预的潜在靶点，因为它在疾病中失调。我们采用开放科学的方法，基于先导化合物 ，开发了一系列有效、选择性、口服生物利用度和脑穿透性的 ALK2 抑制剂。对核心吡啶环的 C-3、C-4 和 C-5 位置取代基进行适度的结构改变，得到了化合物 、 和 ，它们各自具有更高的效力、选择性和/或血脑屏障（BBB）穿透特性。这些抑制剂具有良好的药代动力学（PK）特性和耐受性，标志着它们是适合进一步开发和在 DIPG 的原位模型中进行评估的先进临床前化合物。
