iLeadBMS Co., Ltd., Hwaseong-si, Gyeonggi-do 18469, Republic of Korea; Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Research Laboratories, Ildong Pharmaceutical Co., Hwaseong-si, Gyeonggi-do 445-170, Republic of Korea.
Bioorg Med Chem Lett. 2021 May 15;40:127963. doi: 10.1016/j.bmcl.2021.127963. Epub 2021 Mar 17.
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are rate-limiting enzymes in the kynurenine pathway (KP) of l-tryptophan (l-Trp) metabolism and are becoming key drug targets in the combination therapy of checkpoint inhibitors in immunoncology. To discover a selective and potent IDO1 inhibitor, a structure-activity relationship (SAR) study of N-hydroxybenzofuran-5-carboximidamide as a novel scaffold was investigated in a systematic manner. Among the synthesized compounds, the N-3-bromophenyl derivative 19 showed the most potent inhibition, with an IC value of 0.44 μM for the enzyme and 1.1 μM in HeLa cells. The molecular modeling of 19 with the X-ray crystal structure of IDO1 indicated that dipole-ionic interactions with heme iron, halogen bonding with Cys129 and the two hydrophobic interactions were important for the high potency of 19.
人吲哚胺 2,3-双加氧酶 1（hIDO1）和色氨酸双加氧酶（hTDO）是 l-色氨酸（l-Trp）代谢中犬尿氨酸途径（KP）的限速酶，并且正在成为免疫肿瘤学中检查点抑制剂联合治疗的关键药物靶标。为了发现选择性和有效的 IDO1 抑制剂，我们系统地研究了 N-羟基苯并呋喃-5-甲脒作为一种新型支架的构效关系（SAR）。在所合成的化合物中，N-3-溴苯基衍生物 19 表现出最强的抑制作用，对酶的 IC 值为 0.44 μM，在 HeLa 细胞中的 IC 值为 1.1 μM。与 IDO1 的 X 射线晶体结构的 19 的分子建模表明，与血红素铁的偶极-离子相互作用、与 Cys129 的卤键以及两个疏水相互作用对于 19 的高活性很重要。
