Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
Ref Type | Journal Article | ||||||||||||
PMID | (37743366) | ||||||||||||
Authors | Miyazaki I, Odintsov I, Ishida K, Lui AJW, Kato M, Suzuki T, Zhang T, Wakayama K, Kurth RI, Cheng R, Fujita H, Delasos L, Vojnic M, Khodos I, Yamada Y, Ishizawa K, Mattar MS, Funabashi K, Chang Q, Ohkubo S, Yano W, Terada R, Giuliano C, Lu YC, Bonifacio A, Kunte S, Davare MA, Cheng EH, de Stanchina E, Lovati E, Iwasawa Y, Ladanyi M, Somwar R | ||||||||||||
Title | Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. | ||||||||||||
|
|||||||||||||
URL | |||||||||||||
Abstract Text | 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. |