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

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

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. kitagawa.mayumi.zr@daiichisankyo.co.jp.
  • # 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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