Recent Advances in the Research and Development of B-Raf Inhibitors

Hui-Fang      Li; Yadong      Chen; Sha-Sha      Rao; Xiu-Mei      Chen; Hai-Chun      Liu; Ji-Hong      Qin; Wei-Fang      Tang; Yue-Wang; Xiang      Zhou; Tao      Lu

Abstract

Oncogenic B-Raf has been identified in a variety of cancers with high incidence, especially in malignant melanoma and thyroid cancer. Most B-Raf mutations elicit elevated kinase activity and the constitutive activation of Ras/Raf/MEK/ERK pathway, which induces proliferation and promotes malignant transformation. Therefore, B-Raf inhibitors, targeting B-Raf or mutated B-Raf, have received increasing momentum in oncology drug discovery arena. This review focuses on the diverse small-molecule inhibitors of B-Raf kinase recently reported in the literature, including those currently in clinical and preclinical phase. They are described as two categories, type I or type II kinase inhibitors, based on their different mechanism of action with active or inactive conformations of the B-Raf kinase derived from the available crystal structures or molecular docking analysis. A particular emphasis is placed on their binding modes and the structure-activity relationship (SAR) of each chemical structure class.

Keywords: B-Raf, B-RafV600E, B-Raf kinase inhibitors, binding mode, SAR, mechanism of action