Muraoka Terushige, Ide Mitsuaki, Morikami Kenji, Irie Machiko, Nakamura Mitsuaki, Miura Takaaki, Kamikawa Takayuki, Nishihara Masamichi, Kashiwagi Hirotaka
Research Division, Chugai Pharmaceutical Co,. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Research Division, Chugai Pharmaceutical Co,. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Bioorg Med Chem. 2016 Sep 15;24(18):4206-4217. doi: 10.1016/j.bmc.2016.07.006. Epub 2016 Jul 6.
A novel thienopyrimidinone analog was discovered as a potent and highly selective TAK1 inhibitor using the SBDD approach. TAK1 plays a key role in inflammatory and immune signaling, so TAK1 is considered to be an attractive molecular target for the treatment of human diseases (inflammatory disease, cancer, etc.). After the hit compound had been obtained, our modifications successfully increased TAK1 inhibitory activity and solubility, but metabolic stability was still unsatisfactory. To improve metabolic stability, we conducted metabolic identification. Although the obtained metabolite was fortunately a potent TAK1 inhibitor, its kinase selectivity was low. Subsequently, to achieve high kinase selectivity, we used SBDD to follow two strategies: one targeting unique amino acid residues in TAK1, especially the combination of Ser111 and Asn114; the other decreasing the interaction with Tyr106 at the hinge position in TAK1. As expected, our designed compound showed an excellent kinase selectivity profile in both an in-house and a commercially available panel assay of over 420 kinases and also retained its potent TAK1 inhibitory activity (TAK1 IC50=11nM).
利用基于结构的药物设计（SBDD）方法，发现了一种新型噻吩并嘧啶酮类似物，它是一种强效且高度选择性的TAK1抑制剂。TAK1在炎症和免疫信号传导中起关键作用，因此TAK1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。在获得先导化合物后，我们的修饰成功提高了TAK1抑制活性和溶解度，但代谢稳定性仍不令人满意。为了提高代谢稳定性，我们进行了代谢鉴定。幸运的是，虽然得到的代谢物是一种强效TAK1抑制剂，但其激酶选择性较低。随后，为了实现高激酶选择性，我们利用SBDD采用了两种策略：一种针对TAK1中独特的氨基酸残基，特别是Ser111和Asn114的组合；另一种是减少与TAK1铰链区Tyr106的相互作用。正如预期的那样，我们设计的化合物在内部和市售的超过420种激酶的检测中均显示出优异的激酶选择性谱，并且还保留了其强效的TAK1抑制活性（TAK1 IC50 = 11 nM）。
