Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases
Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases
复制标题
DOI：
10.1021/acs.jmedchem.6b01751
复制
发表时间：
2017-02-23
影响因子：
7.3
通讯作者：
Bertin, John
中科院分区：
文献类型：
--
作者：
Harris, Philip A.;Berger, Scott B.;Bertin, John
RIP1调节坏死性下垂和炎症，并可能在包括免疫介导性炎症性疾病在内的多种人类病理过程中发挥重要作用。适合于进入临床的RIP1激酶小分子抑制剂尚未得到描述。在这里，我们报告了从DNA编码文库中对苯并恶西酮进行的领先优化，以及临床候选化合物GSK2982772(化合物5)的发现和概况，目前该化合物正处于牛皮癣、类风湿性关节炎和溃疡性结肠炎的2a期临床研究中。化合物5能有效地与RIP1结合，具有精致的激酶特异性，并具有良好的阻断许多依赖于肿瘤坏死因子的细胞反应的活性。突出的是，该抑制剂作为一种新型抗炎剂的潜力，还能够减少人类溃疡性结肠炎外植体自发产生的细胞因子。5的高度有利的物理化学和ADMET特性，再加上高效力，导致了预测的人类低口服剂量。
RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting, its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.