The Role of Structural Biology in Kinase Inhibitor Drug Discovery Success

Angiolini, Mauro

doi:10.1002/9781118681121.ch16

Cited by 4 publications

(3 citation statements)

References 227 publications

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“…The end of CR3 facilitates the binding of substrate proteins. This occurs through its catalytic loop, which facilitates the transfer of phosphate from ATP to BRAF substrates [Figure b,c]. , The gatekeeper (catalytic cleft between the N- and C-termini) plays an important role by controlling the access of ligands to a hydrophobic pocket deep in the active site that is not in contact with ATP, which affects the binding and specificity of inhibitors …”

Section: Current Insight Braf Proteinmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Current Insight Braf Proteinmentioning

confidence: 99%

“… 32 , 40 The gatekeeper (catalytic cleft between the N- and C-termini) plays an important role by controlling the access of ligands to a hydrophobic pocket deep in the active site that is not in contact with ATP, which affects the binding and specificity of inhibitors. 41 …”

Section: Current Insight Braf Proteinmentioning

confidence: 99%

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

et al. 2023

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“…The aC-helix near the ATP site is called the aC-IN position, the aC-helix away from the ATP site is called the aC-OUT position. [27][28][29][30][31][32][33] Based on aC-helix and DFG motif, four structural types of inhibitors are currently being developed. ( 1 4) Type I/II, (aC-OUT/DFG-OUT).…”

Section: Different Binding Modes Of Braf Protein With Inhibitorsmentioning

confidence: 99%

Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAF^V600Einhibitors

et al. 2022

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Multistage in silico approach to identify novel quinoline derivatives as potential c-kit kinase inhibitors

Gupta,

Saha,

Singh

et al. 2024

Journal of Biomolecular Structure and Dynamics

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The Role of Structural Biology in Kinase Inhibitor Drug Discovery Success

Cited by 4 publications

References 227 publications

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

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

Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAF^V600Einhibitors

Multistage in silico approach to identify novel quinoline derivatives as potential c-kit kinase inhibitors

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The Role of Structural Biology in Kinase Inhibitor Drug Discovery Success

Cited by 4 publications

References 227 publications

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

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

Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAFV600Einhibitors

Multistage in silico approach to identify novel quinoline derivatives as potential c-kit kinase inhibitors

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Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAF^V600Einhibitors