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Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.
Miyazaki, Isao; Odintsov, Igor; Ishida, Keiji; Lui, Allan J W; Kato, Masanori; Suzuki, Tatsuya; Zhang, Tom; Wakayama, Kentaro; Kurth, Renate I; Cheng, Ryan; Fujita, Hidenori; Delasos, Lukas; Vojnic, Morana; Khodos, Inna; Yamada, Yukari; Ishizawa, Kota; Mattar, Marissa S; Funabashi, Kaoru; Chang, Qing; Ohkubo, Shuichi; Yano, Wakako; Terada, Ryuichiro; Giuliano, Claudio; Lu, Yue Christine; Bonifacio, Annalisa; Kunte, Siddharth; Davare, Monika A; Cheng, Emily H; de Stanchina, Elisa; Lovati, Emanuela; Iwasawa, Yoshikazu; Ladanyi, Marc; Somwar, Romel.
  • Miyazaki I; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan. isao-miyazaki@taiho.co.jp.
  • Odintsov I; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Ishida K; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Lui AJW; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Kato M; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • Suzuki T; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Zhang T; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Wakayama K; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • Kurth RI; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • Cheng R; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Fujita H; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • Delasos L; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Vojnic M; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Khodos I; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • Yamada Y; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Ishizawa K; Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
  • Mattar MS; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Funabashi K; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Chang Q; Northwell Health Cancer Institute, Lenox Hill Hospital, New York, NY, USA.
  • Ohkubo S; Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Yano W; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • Terada R; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Giuliano C; Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan.
  • Lu YC; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Bonifacio A; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • Kunte S; Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Davare MA; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • Cheng EH; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • de Stanchina E; Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • Lovati E; Helsinn Healthcare SA, Lugano, Switzerland.
  • Iwasawa Y; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Ladanyi M; Helsinn Healthcare SA, Lugano, Switzerland.
  • Somwar R; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Cancer ; 4(9): 1345-1361, 2023 09.
Article en En | MEDLINE | ID: mdl-37743366
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas Idioma: En Año: 2023 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas Idioma: En Año: 2023 Tipo del documento: Article