2. Academic Validation
  3. Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance

Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance

  • Eur J Med Chem. 2017 Apr 21:130:86-106. doi: 10.1016/j.ejmech.2017.02.041.
Lu Wang 1,  Qing Zhang 2,  Gaoyuan Zhu 1,  Zhimin Zhang 1,  Yanle Zhi 1,  Li Zhang 1,  Tianxiao Mao 1,  Xiang Zhou 1,  Yadong Chen 1,  Tao Lu 3,  Weifang Tang 4
Affiliations

Affiliations

  • 1 School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
  • 2 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, 211198, China.
  • 3 School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, China. Electronic address: lut163@163.com.
  • 4 School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. Electronic address: twf@cpu.edu.cn.
PMID: 28242553 DOI: 10.1016/j.ejmech.2017.02.041
Abstract

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 BRafWT phenotypic melanoma and BRafV600E phenotypic 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 BRafV600E inhibitor therapy. I-41 also have a favorable pharmacokinetic profile in rat. Synthesis, SAR, lead selection, and evaluation of the key compounds studies are described.

Keywords

PK; Pan-Raf inhibitors; Pyrimidine scaffold; Resistance.

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