We sought to develop a pharmacologically advanced inhibitor of the oncoprotein RET. Vepafestinib potently inhibited on-target mutants that confer resistance to approved RET inhibitors while exerting superior efficacy against intracranial disease due to enhanced penetration and retention in the brain.
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References
Lin, J. J. et al. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer. Ann Oncol. 31, 1725–1733 (2020). This article is a comprehensive analysis of variable on-target and off-target mechanisms of resistance to RET inhibitors.
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This is a summary of: Miyazaki, I. et al. Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. Nat. Cancer https://doi.org/10.1038/s43018-023-00630-y (2023).
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Vepafestinib: a RET-selective inhibitor with enhanced CNS penetrance targets therapy-resistant mutants. Nat Cancer 4, 1220–1221 (2023). https://doi.org/10.1038/s43018-023-00631-x
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DOI: https://doi.org/10.1038/s43018-023-00631-x
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