Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

Ankit Kumar Singh, Pankaj Sonawane, Adarsh Kumar, Harshwardhan Singh, Vladislav Naumovich, Prateek Pathak, Maria Grishina, Habibullah Khalilullah, Mariusz Jaremko, Abdul-Hamid M. Emwas, Amita Verma, Pradeep Kumar

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.
Original languageEnglish (US)
StatePublished - Jul 26 2023

Bibliographical note

KAUST Repository Item: Exported on 2023-07-31
Acknowledgements: The APC was funded by King Abdullah University of Science and Technology, Thuwal, Jeddah, Saudi Arabia. The authors are thankful to DST-FIST, Central University of Punjab, Bathinda, for providing the necessary facilities to execute this manuscript.


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