1086423-48-4Relevant articles and documents
Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance
Wang, Lu,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Zhi, Yanle,Zhang, Li,Mao, Tianxiao,Zhou, Xiang,Chen, Yadong,Lu, Tao,Tang, Weifang
, p. 86 - 106 (2017/03/02)
Simutaneous targeting all Raf isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWTphenotypic melanoma and BRafV600Ephenotypic colon cells. The western blot results for the Erk inhibition in human melanoma SK-Mel-2?cell lines showed I-41 inhibited the proliferation of SK-Mel-2?cell lines without paradoxical activation of Erk, which supported I-41 may become a good candidate compound to overcome the resistance of melanoma against the current BRafV600Einhibitor therapy. I-41 also have a favorable pharmacokinetic profile in rat. Synthesis, SAR, lead selection, and evaluation of the key compounds studies are described.
Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance
Wang, Lu,Zhu, Gaoyuan,Zhang, Qing,Duan, Chunqi,Zhang, Yanmin,Zhang, Zhimin,Zhou, Yujun,Lu, Tao,Tang, Weifang
, p. 3455 - 3465 (2017/04/26)
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.
Potent Pan-Raf and Receptor Tyrosine Kinase Inhibitors Based on a Cyclopropyl Formamide Fragment Overcome Resistance
Zhang, Yanmin,Wang, Lu,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Zhou, Xiang,Chen, Yadong,Lu, Tao,Tang, Weifang
, p. 1439 - 1452 (2017/06/30)
While selective BRafV600E inhibitors have been proven effective clinically, acquired resistance rapidly develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway. Simultaneous targeting of multiple nodes in the pathway offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Replacement pyridine group of Y-1 by a cyclopropyl formamide group afforded I-01 as a novel multitargeted kinase inhibitor template. I-01 displayed enzyme potency against Pan-Raf and receptor tyrosine kinases (RTKs). Based on the binding mode of I-01, analogues I-02-I-18 were designed and synthesized. The most promising compound I-16 potently inhibits all subtypes of Rafs with IC50 values of 3.49 (BRafV600E), 8.86 (ARaf), 5.78 (BRafWT), and 1.65 nM (CRaf), respectively. I-16 not only exhibit comparable antiproliferative activities with positive control compounds against HepG2, SW579, MV4-11, and COLO205 cell lines, but also suppress the proliferation of melanoma SK-MEL-2 harboring overexpressed BRafWT with IC50 values of 0.93 μM. The Western blot results for the ERK inhibition in human melanoma SK-MEL-2 cell lines show that I-16 inhibits the proliferation of SK-MEL-2 cell lines without paradoxical activation of ERK, which support the hypothesis that the inhibition of Pan-Raf and RTKs might be a tractable strategy to overcome the resistance of melanoma induced by the therapy with the current selective BRafV600E inhibitors.
