title: Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance.
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 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.
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, 211198, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Gaoyuan
authors.initials: G
authors.lastname: Zhu
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Yanle
authors.initials: Y
authors.lastname: Zhi
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Mao
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. Electronic address: twf@cpu.edu.cn.
authors.forename: Weifang
authors.initials: W
authors.lastname: Tang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D048490:raf Kinases
keywords: PK; Pan-Raf inhibitors; Pyrimidine scaffold; Resistance