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Issue 16, 2017
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Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance

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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

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Publication details

The article was received on 01 Mar 2017, accepted on 17 Mar 2017 and first published on 20 Mar 2017


Article type: Paper
DOI: 10.1039/C7OB00518K
Citation: Org. Biomol. Chem., 2017,15, 3455-3465
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    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

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