Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations

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Odintsov, Igor 
Ishida, Keiji 

RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.


Acknowledgements: This work was supported by funding from Helsinn Healthcare (to R.S. and M.L.) and grants from the National Institutes of Health to E.d.S. (U54 D020355) and the MSKCC (Cancer Center Support grant P30 CA008748 and Summer Research Experiences Supervised by Faculty Mentors grant 5R25CA020449).

Funder: Helsinn Healthcare, SA

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Nature Cancer
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Nature Publishing Group US
U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) (P30 CA008748, 5R25CA020449, U54 D020355, U54 D020355)