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.
- 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: [email protected].
- 4. School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. Electronic address: [email protected].
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.