Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations
Isao Miyazaki, Igor Odintsov, Keiji Ishida, Allan J.W. Lui, Masanori Kato, Tatsuya Suzuki, Tom Zhang, Kentaro Wakayama, Renate I. Kurth, Ryan R. Cheng, Hidenori Fujita, Lukas Delasos, Morana Vojnic, Inna Khodos, Yukari Yamada, Kota Ishizawa, Marissa S. Mattar, Kaoru Funabashi, Qing Chang, Shuichi Ohkubo, Wakako Yano, Ryuichiro Terada, Claudio Giuliano, Yue Lü, Annalisa Bonifacio, Siddharth Kunte, Monika A. Davare, Emily H. Cheng, Elisa de Stanchina, Emanuela Lovati, Yoshikazu Iwasawa, Marc Ladanyi, Romel Somwar
Abstract
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 RET L730 , RET V804 and RET G810 ), 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.