Tojo Shingo, Kohno Tetsuya, Tanaka Tomoyuki, Kamioka Seiji, Ota Yosuke, Ishii Takayuki, Kamimoto Keiko, Asano Shigehiro, Isobe Yoshiaki
Dainippon Sumitomo Pharma Co., Ltd. , 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
ACS Med Chem Lett. 2014 Aug 21;5(10):1119-23. doi: 10.1021/ml500247w. eCollection 2014 Oct 9.
Indoleamine 2,3-dioxygenase 1 (IDO1) is considered as a promising target for the treatment of several diseases, including neurological disorders and cancer. We report here the crystal structures of two IDO1/IDO1 inhibitor complexes, one of which shows that Amg-1 is directly bound to the heme iron of IDO1 with a clear induced fit. We also describe the identification and preliminary optimization of imidazothiazole derivatives as novel IDO1 inhibitors. Using our crystal structure information and structure-activity relationships (SAR) at the pocket-B of IDO1, we found a series of urea derivatives as potent IDO1 inhibitors and revealed that generation of an induced fit and the resulting interaction with Phe226 and Arg231 are essential for potent IDO1 inhibitory activity. The results of this study are very valuable for understanding the mechanism of IDO1 activation, which is very important for structure-based drug design (SBDD) to discover potent IDO1 inhibitors.
吲哚胺2,3-双加氧酶1（IDO1）被认为是治疗多种疾病的一个有前景的靶点，这些疾病包括神经紊乱和癌症。我们在此报告了两种IDO1/IDO1抑制剂复合物的晶体结构，其中一种显示Amg-1通过明显的诱导契合直接结合到IDO1的血红素铁上。我们还描述了咪唑并噻唑衍生物作为新型IDO1抑制剂的鉴定和初步优化。利用我们的晶体结构信息以及IDO1口袋-B处的构效关系（SAR），我们发现了一系列脲衍生物作为有效的IDO1抑制剂，并揭示诱导契合的产生以及由此与苯丙氨酸226和精氨酸231的相互作用对于有效的IDO1抑制活性至关重要。这项研究的结果对于理解IDO1激活机制非常有价值，这对于基于结构的药物设计（SBDD）以发现有效的IDO1抑制剂非常重要。
