Structure-based de novo design and biochemical evaluation of novel BRAF kinase inhibitors

VRAF murine sarcoma viral oncogene homologue B1 (BRAF) kinase has been considered to be a promising therapeutic target for various human cancers. We have been able to identify 24 novel BRAF kinase inhibitors with K(d) values ranging from 0.4 to 10μM utilizing a structure-based de novo design method with the two known inhibitor scaffolds. Because these discovered inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further investigation as anticancer agents. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of BRAF are discussed in detail.