title: Discovery and pharmacophore studies of novel pyrazole-based anti-melanoma agents.
abstract: Due to the rising incidence and lack of effective treatments, malignant melanoma is the most dangerous form of skin cancer, so that new treatment strategies are urgently needed. Several recent developments indicate that the V600E mutant BRAF (BRAF(V600E) ) is a validated target for antimelanoma-drug development. Based on in silico screening results, a series of novel pyrazole derivatives has been designed, synthesized, and evaluated in vitro for their inhibitory activities against BRAF(V600E) melanoma cells. Compound 3d exhibited the most potent inhibitory activity with an IC50 value of 0.63 μM for BRAF(V600E) and a GI50 value of 0.61 μM for mutant BRAF-dependent cells. Furthermore, the QSAR modeling and the docking simulation of inhibitor analogs provide important pharmacophore clues for further structural optimization.
authors: School of Medical Engineering, Hefei University of Technology, Hefei 230009, P. R. China, (phone/fax: +86-551-62904675); Key Laboratory of Green Pesticide and Agriculture Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, P. R. China. liqs@hfut.edu.cn.
authors: Qing-Shan
authors: QS
authors: Li
authors: Xian-Hai
authors: XH
authors: Lü
authors: Yang
authors: Y
authors: Yang
authors: Ban-Feng
authors: BF
authors: Ruan
authors: Ri-Sheng
authors: RS
authors: Yao
authors: Chen-Zhong
authors: CZ
authors: Liao
mesh_terms: D055808:Drug Discovery; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D011720:Pyrazoles; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: 1H-Pyrazoles, 3,5-diaryl-4,5-dihydro-; Melanoma; Nicotinamide; Quantitative structureactivity relationship (QSAR); Urea