Journal of Medicinal Chemistry p. 8325 - 8337 (2020)
Update date:2022-07-29
Topics:
Sarkar, Dhruba
Olejniczak, Edward T.
Phan, Jason
Coker, Jesse A.
Sai, Jiqing
Arnold, Allison
Beesetty, Yugandhar
Waterson, Alex G.
Fesik, Stephen W.
The nucleotide exchange factor Son of Sevenless (SOS) catalyzes the activation of RAS by converting it from its inactive GDP-bound state to its active GTP-bound state. Recently, we have reported the discovery of small-molecule allosteric activators of SOS1 that can increase the amount of RAS-GTP in cells. The compounds can inhibit ERK phosphorylation at higher concentrations by engaging a feedback mechanism. To further study this process, we sought different chemical matter from an NMR-based fragment screen using selective methyl labeling. To aid this process, several Ile methyl groups located in different binding sites of the protein were assigned and used to categorize the NMR hits into different classes. Hit to lead optimization using an iterative structure-based design paradigm resulted in compounds with improvements in binding affinity. These improved molecules of a different chemical class increase SOS1cat-mediated nucleotide exchange on RAS and display cellular action consistent with our prior results.
View MoreContact:+86-579-85206992
Address:No 451 chouzhou north road ,room 1106 int'l business center , yiwu ,china
Tianjin Ingenochem Technology Co.,Ltd
Contact:+86-22-23677060
Address:Hitech Green Industry Park K2-9-602, Nankai district
guide(suzhou) fine materials co. ltd
Contact:0512-80972173
Address:21st Building, No.369 Lushan Rd, New District Suzhou China 215129
JiangXi Hong Run Chemical Co., Ltd
Contact:+86-0791-88521351
Address:XingHuo industrial zone in YongXiu county
Contact:86-791-86629460
Address:1-6F, 118 Xinzhou road, Nanchang, Jiangxi, China
Doi:10.1021/ol100037c
(2010)Doi:10.3390/molecules25194494
(2020)Doi:10.1021/jm9606406
(1997)Doi:10.1016/j.tet.2009.11.108
(2010)Doi:10.1007/s00706-010-0388-z
(2010)Doi:10.1016/j.tetlet.2009.12.123
(2010)