Author:
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
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 < 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).
Funder
Daiichi Sankyo Co., Ltd
Chugai Pharmaceutical Co., Ltd
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Oncology
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