Title:Mutant B-Raf Kinase Inhibitors as Anticancer Agents
Volume: 16
Issue: 12
Author(s): Vivek Asati, Sanjay K. Bharti and Debarshi K. Mahapatra
Affiliation:
Keywords:
B-Raf, cancer, clinical trials, inhibitors, SARs, signaling pathways.
Abstract: The Ras/Raf/MEK/ERK signaling pathway involves various kinases in which each
kinase is associated with one another through signals and regulates cell proliferation, differentiation
and apoptosis. This pathway is dysregulated almost in all cancers due to the amplification and
genetic mutation of various components of the pathway. The genetic mutations have been
reported to cause drug resistance to the current chemotherapy of melanomas. B-Raf is one of the
most commonly mutated proto-oncogenes and plays a significant role in the development of
numerous cancers of high clinical impact. Therefore, mutant B-Raf kinase may be a promising
therapeutic target for the development of novel anticancer drugs. Many BRAF inhibitors
discovered during the last decade showed promising anticancer activity, especially on tumors
that harbor BRAFV600E mutations. Currently, vemurafenib and dabrafenib are USFDA
approved drugs used as B-Raf inhibitors. Few drugs which are under clinical development
phases such as LGX818, GDC0879, XL281, ARQ736, PLX3603 (RO5212054), and RAF265
etc. pave the path for further designing of B-Raf inhibitors. The present review focuses primarily
on the Ras/Raf/MEK/ERK signaling pathway with mutant B-Raf as a therapeutic target for anticancer drug
development. The essential pharmacophoric features of B-Raf inhibitors, their structure activity relationships (SARs)
and molecules under clinical trials have been highlighted.
