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

  • Cancer Cell Int. 2023 Feb 25;23(1):36. doi: 10.1186/s12935-023-02877-y.
Masashi Numata  #  1 ,  Noriyasu Haginoya  #  2 ,  Machiko Shiroishi  1 ,  Tsuyoshi Hirata  2 ,  Aiko Sato-Otsubo  3  4 ,  Kenji Yoshikawa  1 ,  Yoshimi Takata  1 ,  Reina Nagase  1 ,  Yoshinori Kashimoto  2 ,  Makoto Suzuki  2 ,  Nina Schulte  5 ,  Gernot Polier  5 ,  Akiko Kurimoto  1 ,  Yumiko Tomoe  1 ,  Akiko Toyota  1 ,  Tomoko Yoneyama  2 ,  Emi Imai  2 ,  Kenji Watanabe  1 ,  Tomoaki Hamada  1 ,  Ryutaro Kanada  1 ,  Jun Watanabe  1 ,  Yoshiko Kagoshima  1 ,  Eri Tokumaru  1 ,  Kenji Murata  1 ,  Takayuki Baba  1 ,  Taeko Shinozaki  1 ,  Masami Ohtsuka  1 ,  Koichi Goto  1 ,  Tsuyoshi Karibe  1 ,  Takao Deguchi  6 ,  Yoshihiro Gocho  6 ,  Masanori Yoshida  3 ,  Daisuke Tomizawa  6 ,  Motohiro Kato  3  4  6 ,  Shinji Tsutsumi  1 ,  Mayumi Kitagawa  7 ,  Yuki Abe  1
Affiliations
  • 1. Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan.
  • 2. Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan.
  • 3. Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
  • 4. Department of Pediatrics, University of Tokyo, Tokyo, Japan.
  • 5. Daiichi Sankyo Europe GmbH, Munich, Germany.
  • 6. Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
  • 7. Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-5 Hiromachi, Shinagawa-Ku, Tokyo, 140-0005, Japan. [email protected].
  • # Contributed equally.
PMID: 36841758 DOI: 10.1186/s12935-023-02877-y
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).

Keywords
Leukemia-initiating cells; MLL1-r or NPM1c acute leukemia; Menin-MLL1 inhibitor.
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