Recently I am researching about MULTIKINASE INHIBITOR; DISCOVERY; RESISTANCE; SORAFENIB; MUTATIONS; PATHWAY, Saw an article supported by the National Science FoundationNational Science Foundation (NSF) [CHE-1455306]; Canadian Cancer Society Research InstituteCanadian Cancer Society (CCS) [704116]; Canada Research Chair ProgramCanada Research Chairs; Canadian Institutes for Health ResearchCanadian Institutes of Health Research (CIHR) [FDN143277]; Stauffer Endowed Fellowship, USC Graduate School; USC Dornsife Chemical Biology Training Program; TD Bank postdoctoral fellowship; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) – USANIH National Institute of General Medical Sciences (NIGMS) [P30GM124165] Funding Source: NIH RePORTER. Published in AMER CHEMICAL SOC in WASHINGTON ,Authors: Assadieskandar, A; Yu, CQ; Maisonneuve, P; Kunnov, I; Sicheri, F; Zhang, C. The CAS is 98-17-9. Through research, I have a further understanding and discovery of 3-(Trifluoromethyl)phenol. Category: indole-building-block
One effective means to achieve inhibitor specificity for RAF kinases, an important family of cancer drug targets, has been to target the monomeric inactive state conformation of the kinase domain, which, unlike most other kinases, can accommodate sulfonamide-containing drugs such as vemurafenib and dabrafenib because of the presence of a unique pocket specific to inactive RAF kinases. We previously reported an alternate strategy whereby rigidification of a nonselective pyrazolo[3,4-d]pyrimidine-based inhibitor through ring closure afforded moderate but appreciable increases in selectivity for RAF kinases. Here, we show that a further application of the rigidification strategy to a different pyrazolopyrimidine-based scaffold dramatically improved selectivity for RAF kinases. Crystal structure analysis confirmed our inhibitor design hypothesis revealing that 21 engages an active-like state conformation of BRAF normally associated with poorly discriminating inhibitors. When screened against a panel of distinct cancer cell lines, the optimized inhibitor 21 primarily inhibited the proliferation of the expected BRAF(V600E)-harboring cell lines consistent with its kinome selectivity profile. These results suggest that rigidification could be a general and powerful strategy for enhancing inhibitor selectivity against protein kinases, which may open up therapeutic opportunities not afforded by other approaches.
Category: indole-building-block. About 3-(Trifluoromethyl)phenol, If you have any questions, you can contact Assadieskandar, A; Yu, CQ; Maisonneuve, P; Kunnov, I; Sicheri, F; Zhang, C or concate me.
Reference:
Indole alkaloid derivatives as building blocks of natural products from Bacillus thuringiensis and Bacillus velezensis and their antibacterial and antifungal activity study,
,Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles