Jump to main content
Jump to site search
PLANNED MAINTENANCE Close the message box

Scheduled maintenance work on Wednesday 21st October 2020 from 07:00 AM to 07:00 PM (BST).

During this time our website performance may be temporarily affected. We apologise for any inconvenience this might cause and thank you for your patience.


Issue 16, 2017
Previous Article Next Article

Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance

Author affiliations

Abstract

Selective BRafV600E inhibitors with DFG-in conformation have been proven effective against a subset of melanoma. However, representative inhibitor vemurafenib rapidly acquires resistance in the BRafWT cells through a CRaf or BRafWT dependent manner. Simultaneous targeting of all subtypes of Raf proteins offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Herein, we describe the design and characterization of a series of compounds I-01–I-22, based on a pyrimidine scaffold with DFG-out conformation as Pan-Raf inhibitors. Among them, I-15 binds to all Raf protomers with IC50 values of 12.6 nM (BRafV600E), 30.1 nM (ARaf), 19.7 nM (BRafWT) and 17.5 nM (CRaf) and demonstrates cellular activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colorectal cancer cells. The western blot results for the P-Erk inhibition in human melanoma SK-Mel-2 cell line showed that I-15 inhibited the proliferation of the SK-Mel-2 cell line at concentrations as low as 400 nM, without paradoxical activation of Erk as vemurafenib, which supported that I-15 may become a good candidate compound to overcome the resistance of melanoma induced by vemurafenib. I-15 also has a favorable pharmacokinetic profile in rats. Rational design, synthesis, SAR, lead selection and evaluation of the key compounds studied are described.

Graphical abstract: Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance

Back to tab navigation

Supplementary files

Article information


Submitted
01 Mar 2017
Accepted
17 Mar 2017
First published
20 Mar 2017

Org. Biomol. Chem., 2017,15, 3455-3465
Article type
Paper

Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance

L. Wang, G. Zhu, Q. Zhang, C. Duan, Y. Zhang, Z. Zhang, Y. Zhou, T. Lu and W. Tang, Org. Biomol. Chem., 2017, 15, 3455
DOI: 10.1039/C7OB00518K

Social activity

Search articles by author

Spotlight

Advertisements