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

Abstract

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 (BRAF V600 ), 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.

Mutations in the Serine/Threonine Kinase BRAF: Oncogenic Drivers in Solid Tumors

“…Specifically, they bind the inactive-OUT position of the αC helix [ 54 ]. Second-generation RAF inhibitors can also be effective against other Class I BRAF mutations, which include all V600 variants and make up over 90% of all BRAF mutations [ 32 ]. Class I BRAF mutations are highly kinase-active, RAS-independent, and signal as monomers [ 136 ].…”

“…Notably, BRAF mutations are seen at particularly high rates in melanoma, colorectal cancer (CRC), lung cancer, and papillary thyroid carcinomas (PTCs) [ 15 , 26 , 27 , 28 , 29 , 30 , 31 ] ( Figure 4 a). Specifically, BRAF-activating mutations are primarily limited to the kinase domain, encompassing exons 11 to 15 [ 32 ] ( Figure 4 b). Among the various BRAF mutations, exon 15 p.V600E is by far the most prevalent [ 15 ] ( Figure 4 b).…”

Role and Function of Receptor Tyrosine Kinases in BRAF Mutant Cancers

“…Notably, vemurafenib was also active against brain metastases of V600 mutant melanomas [52]. The selective BRAF-inhibitors dabrafenib and encorafenib were approved thereafter, and various third-generation inhibitors have meanwhile entered clinical trials [53]. In the light of emerging resistance to monotherapies with vemurafenib or dabrafenib, the combination of dabrafenib with the MEK inhibitor trametinib (also known as mekinist) was evaluated in metastatic melanoma and was clinically approved for the treatment of V600 mutant melanoma and NSCLC [54,55].…”

Transcytosis-Driven Treatment of Neurodegenerative Disorders by mRNA-Expressed Antibody–Transferrin Conjugates

“…Additionally, the linker should be designed to be cleavable within the unique microenvironment of the BBB, which may have different enzymatic activities or pH compared to other tissues [76]. Once a linker design is proposed, it is crucial to validate its efficacy in facilitating brain entry and cleavage in preclinical models [77]. Optimization may be necessary to achieve the desired pharmacokinetics and brain distribution.…”