Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Pharmaron Beijing Co., Ltd . 6 Taihe Road, BDA, Beijing 100176, P.R. China.
J Med Chem. 2017 Jan 26;60(2):627-640. doi: 10.1021/acs.jmedchem.6b01363. Epub 2017 Jan 12.
We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).
我们在此报告了一种新型 NF-κB 诱导激酶 (NIK) 抑制剂的基于结构的优化。从一个中等效力、低分子量的先导化合物开始，通过设计一种 11/2 型结合模式，该模式可以进入甲硫氨酸 471 位的“守门员”后面的后口袋，从而提高了活性。在 NIK 和 PI3K 中利用不同的结合模式来抑制 PI3K 抑制，同时在这些系列中保持对 NIK 的抑制。发现了具有选择性抑制 NF-κB2（p52/REL-B）而不是经典 NF-κB1（REL-A/p50）核易位的有效化合物。
