Muraoka Terushige, Ide Mitsuaki, Irie Machiko, Morikami Kenji, Miura Takaaki, Nishihara Masamichi, Kashiwagi Hirotaka
Research Division, Chugai Pharmaceutical Co., Ltd.
Chem Pharm Bull (Tokyo). 2016;64(11):1622-1629. doi: 10.1248/cpb.c16-00606.
We have developed a method for converting a transforming growth factor-β-activated kinase 1 (TAK1) type I inhibitor into a type II or c-helix-out inhibitor by structure-based drug design (SBDD) to achieve an effective strategy for developing these different types of kinase inhibitor in parallel. TAK1 plays a key role in inflammatory and immune signaling, and is therefore considered to be an attractive molecular target for the treatment of human diseases (inflammatory disease, cancer, etc.). We have already reported novel type I TAK1 inhibitor, so we utilized its X-ray information to design a new chemical class type II and c-helix-out inhibitors. To develop the type II inhibitor, we superimposed the X-ray structure of our reported type I inhibitor onto a type II compound that inhibits multiple kinases, and used SBDD to design a new type II inhibitor. For the TAK1 c-helix-out inhibitor, we utilized the X-ray structure of a b-Raf c-helix-out inhibitor to design compounds, because TAK1 is located close to b-Raf in the Sugen kinase tree, so we considered that TAK1 would, similarly to b-Raf, form a c-helix-out conformation. The X-ray crystal structure of the inhibitors in complex with TAK1 confirmed the binding modes of the compounds we designed. This report is notable for being the first discovery of a c-helix-out inhibitor against TAK1.
我们已经开发出一种方法，通过基于结构的药物设计（SBDD）将转化生长因子-β激活激酶1（TAK1）I型抑制剂转化为II型或c-螺旋外抑制剂，以实现并行开发这些不同类型激酶抑制剂的有效策略。TAK1在炎症和免疫信号传导中起关键作用，因此被认为是治疗人类疾病（炎症性疾病、癌症等）的一个有吸引力的分子靶点。我们已经报道了新型I型TAK1抑制剂，因此我们利用其X射线信息来设计新的化学类别II型和c-螺旋外抑制剂。为了开发II型抑制剂，我们将我们报道的I型抑制剂的X射线结构叠加到一种抑制多种激酶的II型化合物上，并使用SBDD设计一种新的II型抑制剂。对于TAK1 c-螺旋外抑制剂，我们利用b-Raf c-螺旋外抑制剂的X射线结构来设计化合物，因为在Sugen激酶树中TAK1与b-Raf位置相近，所以我们认为TAK将与b-Raf类似，形成c-螺旋外构象。抑制剂与TAK1复合物的X射线晶体结构证实了我们设计的化合物的结合模式。本报告的亮点在于首次发现了针对TAK1的c-螺旋外抑制剂。
