Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations Journal Article
| Authors: | Miyazaki, I.; Odintsov, I.; Ishida, K.; Lui, A. J. W.; Kato, M.; Suzuki, T.; Zhang, T.; Wakayama, K.; Kurth, R. I.; Cheng, R.; Fujita, H.; Delasos, L.; Vojnic, M.; Khodos, I.; Yamada, Y.; Ishizawa, K.; Mattar, M. S.; Funabashi, K.; Chang, Q.; Ohkubo, S.; Yano, W.; Terada, R.; Giuliano, C.; Lu, Y. C.; Bonifacio, A.; Kunte, S.; Davare, M. A.; Cheng, E. H.; de Stanchina, E.; Lovati, E.; Iwasawa, Y.; Ladanyi, M.; Somwar, R. |
| Article Title: | Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations |
| Abstract: | 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. © 2023, The Author(s). |
| Keywords: | signal transduction; controlled study; human cell; mutation; advanced cancer; nonhuman; brain tumor; brain neoplasms; animal cell; mouse; animal; animals; animal tissue; cell viability; apoptosis; tumor volume; protein kinase inhibitor; animal experiment; animal model; caspase 3; antineoplastic activity; tumor xenograft; central nervous system; protein tyrosine kinase inhibitor; protein kinase inhibitors; brain; western blotting; breast cancer resistance protein; blood brain barrier; vandetanib; brain metastasis; immunoblotting; cancer control; cyclin d1; x ray crystallography; protein ret; solvent; solvents; x ray diffraction; crystallography; pharmacokinetic parameters; prefrontal cortex; metastasis inhibition; caspase 7; cabozantinib; gain of function mutation; human; male; female; article; hek293 cell line; ic50; pralsetinib; selpercatinib; coleoptera; enbezotinib; vepafestinib; beetle |
| Journal Title: | Nature Cancer |
| Volume: | 4 |
| Issue: | 9 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2023-09-01 |
| Start Page: | 1345 |
| End Page: | 1361 |
| Language: | English |
| DOI: | 10.1038/s43018-023-00630-y |
| PUBMED: | 37743366 |
| PROVIDER: | scopus |
| PMCID: | PMC10518257 |
| DOI/URL: | |
| Notes: | Article -- Erratum issued, see DOI: 10.1038/s43018-023-00663-3 -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Romel Somwar -- Source: Scopus |
