Synthesis and biological evaluation of novel N-(5-phenyl-1H-pyrazol-3-yl)benzenesulfonamide derivatives as potential BRAFV600E inhibitors
A series of novel N-(5-phenyl-1H-pyrazol-3-yl)benzenesulfonamide derivatives (5a–5l) were synthesized and developed as potential BRAFV600E inhibitors. Among them, compound 5l exhibited the most potent inhibitory activity with an IC50 value of 0.18 μM for BRAFV600E. Antiproliferative assay results indicated that compound 5l have higher antiproliferative activity against WM266.4 and A375 in vitro with IC50 value of 1.58 and 2.04 μM, respectively, which were comparable with the positive control vemurafenib. Molecular docking of 5l into the BRAFV600E active site was performed to determine the probable binding mode.
KeywordsBRAFV600E inhibitor Pyrazole Molecular docking Antiproliferative
The authors are very much grateful to Nantong University, for providing laboratory facility.
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Conflict of interest
The authors declare that they have no competing interests.
- Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954CrossRefPubMedGoogle Scholar
- Hoeflich KP, Herter S, Tien J, Wong L, Berry L, Chan J et al. (2009) Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res 69:3042–3051CrossRefPubMedGoogle Scholar
- Suijkerbuijk BM, Niculescu-Duvaz I, Gaulon C, Dijkstra HP, Niculescu-Duvaz D, Ménard D et al. (2010) Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): increasing cellular potency through optimization of a distal heteroaromatic group. J Med Chem 53:2741–2756CrossRefPubMedGoogle Scholar