論文 - 詳細
| RRC ID | 76936 |
|---|---|
| 著者 | 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. |
| タイトル | Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. |
| ジャーナル | Nat Cancer |
| 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. |
| 巻・号 | 4(9) |
| ページ | 1345-1361 |
| 公開日 | 2023-9-1 |
| DOI | 10.1038/s43018-023-00630-y |
| PII | 10.1038/s43018-023-00630-y |
| PMID | 37743366 |
| PMC | PMC10518257 |
| MeSH | Brain Brain Neoplasms* Mutation Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use Solvents |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 15 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3(RCB4476) LC-2/ad(RCB0440) |