A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1

Cancer Cell International

Research

Yoshihiro Gocho¹  Daisuke Tomizawa¹  Takao Deguchi¹  Nina Schulte²  Gernot Polier²  Tomoko Yoneyama³  Makoto Suzuki³  Yoshinori Kashimoto³  Noriyasu Haginoya³  Emi Imai³  Tsuyoshi Hirata³  Masanori Yoshida⁴  Aiko Sato-Otsubo⁵  Motohiro Kato⁶  Tsuyoshi Karibe⁷  Machiko Shiroishi⁷  Jun Watanabe⁷  Kenji Yoshikawa⁷  Kenji Watanabe⁷  Akiko Toyota⁷  Koichi Goto⁷  Shinji Tsutsumi⁷  Yoshimi Takata⁷  Mayumi Kitagawa⁷  Taeko Shinozaki⁷  Akiko Kurimoto⁷  Masami Ohtsuka⁷  Reina Nagase⁷  Yumiko Tomoe⁷  Eri Tokumaru⁷  Masashi Numata⁷  Ryutaro Kanada⁷  Kenji Murata⁷  Yuki Abe⁷  Tomoaki Hamada⁷  Yoshiko Kagoshima⁷  Takayuki Baba⁷ 

[1] Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan;Daiichi Sankyo Europe GmbH, Munich, Germany;Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan;Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan;Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan;Department of Pediatrics, University of Tokyo, Tokyo, Japan;Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan;Department of Pediatrics, University of Tokyo, Tokyo, Japan;Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan;Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, 140-0005, Tokyo, Japan;

关键词: Menin-MLL1 inhibitor;    MLL1-r;    Leukemia-initiating cells;   

DOI  :  10.1186/s12935-023-02877-y

 received in 2022-09-13, accepted in 2023-02-17,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMixed 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.MethodsWe 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.ResultsOur 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.ConclusionWe 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).

【 授权许可】

CC BY   
© The Author(s) 2023

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