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:10.1186/s12935-023-02877-y

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.

Authors

Masashi Numata^#¹, Noriyasu Haginoya^#², Machiko Shiroishi¹, Tsuyoshi Hirata², Aiko Sato-Otsubo^{3

4}, Kenji Yoshikawa¹, Yoshimi Takata¹, Reina Nagase¹, Yoshinori Kashimoto², Makoto Suzuki², Nina Schulte⁵, Gernot Polier⁵, Akiko Kurimoto¹, Yumiko Tomoe¹, Akiko Toyota¹, Tomoko Yoneyama², Emi Imai², Kenji Watanabe¹, Tomoaki Hamada¹, Ryutaro Kanada¹, Jun Watanabe¹, Yoshiko Kagoshima¹, Eri Tokumaru¹, Kenji Murata¹, Takayuki Baba¹, Taeko Shinozaki¹, Masami Ohtsuka¹, Koichi Goto¹, Tsuyoshi Karibe¹, Takao Deguchi⁶, Yoshihiro Gocho⁶, Masanori Yoshida³, Daisuke Tomizawa⁶, Motohiro Kato^{3

4

6}, Shinji Tsutsumi¹, Mayumi Kitagawa⁷, Yuki Abe¹

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.

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.

Associated data

ClinicalTrials.gov/NCT04752163