1. A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1
- Author
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Masashi Numata, Noriyasu Haginoya, Machiko Shiroishi, Tsuyoshi Hirata, Aiko Sato-Otsubo, Kenji Yoshikawa, Yoshimi Takata, Reina Nagase, Yoshinori Kashimoto, Makoto Suzuki, Nina Schulte, Gernot Polier, Akiko Kurimoto, Yumiko Tomoe, Akiko Toyota, Tomoko Yoneyama, Emi Imai, Kenji Watanabe, Tomoaki Hamada, Ryutaro Kanada, Jun Watanabe, Yoshiko Kagoshima, Eri Tokumaru, Kenji Murata, Takayuki Baba, Taeko Shinozaki, Masami Ohtsuka, Koichi Goto, Tsuyoshi Karibe, Takao Deguchi, Yoshihiro Gocho, Masanori Yoshida, Daisuke Tomizawa, Motohiro Kato, Shinji Tsutsumi, Mayumi Kitagawa, and Yuki Abe
- Subjects
Menin-MLL1 inhibitor ,MLL1-r or NPM1c acute leukemia ,Leukemia-initiating cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract 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
- Published
- 2023
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