Current Insights of BRAF Inhibitors in Cancer

Abstract

Oncogenic BRAF kinase deregulates the ERK signaling pathway in a large number of human tumors. FDA-approved BRAF inhibitors for BRAFV600E/K tumors have provided impressive clinical responses extending survival of melanoma patients. However, these drugs display paradoxical activation in normal tissue with BRAFWT due to RAF transactivation and priming, acquired drug resistance, and limited clinical effectiveness in non-V600 BRAF-dependent tumors, underscoring the urgent need to develop improved BRAF inhibitors. This review provides an overview of recent structural and biochemical insights into the mechanisms of BRAF regulation by BRAF inhibitors that are linked to their clinical activity, clinical liabilities, and medicinal chemistry properties. The effectiveness and challenges of structurally diverse next generation RAF inhibitors currently in preclinical and clinical development are discussed, along with mechanistic insights for developing more effective RAF inhibitors targeting different oncogenic BRAF conformations.

Biochemical Characterization of Full‐Length Oncogenic BRAFV600E together with Molecular Dynamics Simulations Provide Insight into the Activation and Inhibition Mechanisms of RAF Kinases

“…However, the same BRAF inhibitors unexpectedly provoke the so‐called paradoxical activation of MAPK signaling and induce secondary malignancies in melanoma patients carrying activating RAS mutations . These concerns surrounding current BRAF inhibitor therapy underscore the need for further investigation to elucidate the mechanisms that modulate the MAPK signaling …”

Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases

“…B-Raf is the most studied of the three human Raf kinases, because more than 50% of human melanomas contain an activating mutation (Val 600 →Glu or V600E) in B-Raf (9). A breakthrough in the treatment of melanoma occurred with the development of small-molecule inhibitors that are effective against the V600E variant of B-Raf (10,11). Unexpectedly, these inhibitors were found to activate signaling through activation of wild-type Raf isoforms (12)(13)(14).…”

Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation

“…These drugs target the signal transduction pathways stimulated by binding of growth factors to their receptors that then result in activation of Ras proteins. Oncogenic Ras signaling occurs in about 30% of all human cancers and triggers homo-or hetero-dimerization of Raf-kinases that is critical for several aspects of signal propagation through downstream MEK and ERK kinases 5,6 . Despite intense efforts, pharmacologic inhibition of RAS proteins themselves and inhibition of their downstream effector kinases has so far been unsuccessful in treating RAS-driven tumors.…”