title: Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance.
abstract: Selective BRafV600Einhibitors with DFG-in conformation have been proven effective against a subset of melanoma. However, representative inhibitor vemurafenib rapidly acquires resistance in the BRafWTcells through a CRaf or BRafWTdependent 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 IC50values of 12.6 nM (BRafV600E), 30.1 nM (ARaf), 19.7 nM (BRafWT) and 17.5 nM (CRaf) and demonstrates cellular activity against BRafWTphenotypic melanoma and BRafV600Ephenotypic 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.
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. lut163@163.com twf@cpu.edu.cn.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Gaoyuan
authors.initials: G
authors.lastname: Zhu
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Chunqi
authors.initials: C
authors.lastname: Duan
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Weifang
authors.initials: W
authors.lastname: Tang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf