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A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1.
Numata, Masashi; Haginoya, Noriyasu; Shiroishi, Machiko; Hirata, Tsuyoshi; Sato-Otsubo, Aiko; Yoshikawa, Kenji; Takata, Yoshimi; Nagase, Reina; Kashimoto, Yoshinori; Suzuki, Makoto; Schulte, Nina; Polier, Gernot; Kurimoto, Akiko; Tomoe, Yumiko; Toyota, Akiko; Yoneyama, Tomoko; Imai, Emi; Watanabe, Kenji; Hamada, Tomoaki; Kanada, Ryutaro; Watanabe, Jun; Kagoshima, Yoshiko; Tokumaru, Eri; Murata, Kenji; Baba, Takayuki; Shinozaki, Taeko; Ohtsuka, Masami; Goto, Koichi; Karibe, Tsuyoshi; Deguchi, Takao; Gocho, Yoshihiro; Yoshida, Masanori; Tomizawa, Daisuke; Kato, Motohiro; Tsutsumi, Shinji; Kitagawa, Mayumi; Abe, Yuki.
Afiliación
  • Numata M; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Haginoya N; Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan.
  • Shiroishi M; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Hirata T; Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan.
  • Sato-Otsubo A; Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
  • Yoshikawa K; Department of Pediatrics, University of Tokyo, Tokyo, Japan.
  • Takata Y; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Nagase R; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Kashimoto Y; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Suzuki M; Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan.
  • Schulte N; Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan.
  • Polier G; Daiichi Sankyo Europe GmbH, Munich, Germany.
  • Kurimoto A; Daiichi Sankyo Europe GmbH, Munich, Germany.
  • Tomoe Y; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Toyota A; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Yoneyama T; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Imai E; Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan.
  • Watanabe K; Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan.
  • Hamada T; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Kanada R; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Watanabe J; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Kagoshima Y; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Tokumaru E; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Murata K; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Baba T; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Shinozaki T; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Ohtsuka M; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Goto K; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Karibe T; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Deguchi T; Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • Gocho Y; Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
  • Yoshida M; Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
  • Tomizawa D; Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
  • Kato M; Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
  • Tsutsumi S; Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
  • Kitagawa M; Department of Pediatrics, University of Tokyo, Tokyo, Japan.
  • Abe Y; Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
Cancer Cell Int ; 23(1): 36, 2023 Feb 25.
Article en En | MEDLINE | ID: mdl-36841758
BACKGROUND: Mixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex. Small-molecule-mediated inhibition of the protein‒protein interaction between Menin and MLL1 fusion proteins is a potential therapeutic strategy for patients with MLL1-r or mutated-nucleophosmin 1 (NPM1c) acute leukemia. In this study, we preclinically evaluated the new compound DS-1594a and its salts. METHODS: We evaluated the preclinical efficacy of DS-1594a as well as DS-1594a·HCl (the HCl salt of DS-1594a) and DS-1594a·succinate (the succinic acid salt of DS-1594a, DS-1594b) in vitro and in vivo using acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) models. RESULTS: Our results showed that MLL1-r or NPM1c human leukemic cell lines were selectively and highly sensitive to DS-1594a·HCl, with 50% growth inhibition values < 30 nM. Compared with cytrabine, the standard chemotherapy drug as AML therapy, both DS-1594a·HCl and DS-1594a·succinate mediated the eradication of potential leukemia-initiating cells by enhancing differentiation and reducing serial colony-forming potential in MLL1-r AML cells in vitro. The results were confirmed by flow cytometry, RNA sequencing, RT‒qPCR and chromatin immunoprecipitation sequencing analyses. DS-1594a·HCl and DS-1594a·succinate exhibited significant antitumor efficacy and survival benefit in MOLM-13 cell and patient-derived xenograft models of MLL1-r or NPM1c acute leukemia in vivo. CONCLUSION: We have generated a novel, potent, orally available small-molecule inhibitor of the Menin-MLL1 interaction, DS-1594a. Our results suggest that DS-1594a has medicinal properties distinct from those of cytarabine and that DS-1594a has the potential to be a new anticancer therapy and support oral dosing regimen for clinical studies (NCT04752163).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancer Cell Int Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancer Cell Int Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido