Recent advances in the research and development of B-Raf inhibitors.

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.

Virtual screening for Raf-1 kinase inhibitors based on pharmacophore model of substituted ureas.

A three-dimensional (3D) quantitative pharmacophore model was developed from a training set of structurally diverse substituted ureas against Raf-1 kinase, which was well validated to be highly predictive by two methods, namely, test set prediction and Cat-Scramble method. Then a virtual database searching was performed with the pharmacophore model as a 3D query, and the bioactivities of the retrieved hits were predicted by the pharmacophore. Subsequently, molecular docking was carried out on the selected hits whose estimated IC(50) was less than 1 microM.