Cancer Cell International (Feb 2023)

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

  • 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,
  • Yuki Abe

DOI
https://doi.org/10.1186/s12935-023-02877-y
Journal volume & issue
Vol. 23, no. 1
pp. 1 – 16

Abstract

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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).

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