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

被引：19

作者：

Numata, Masashi ^{[1
]}

Haginoya, Noriyasu ^{[2
]}

Shiroishi, Machiko ^{[1
]}

Hirata, Tsuyoshi ^{[2
]}

Sato-Otsubo, Aiko ^{[3
,4
]}

Yoshikawa, Kenji ^{[1
]}

Takata, Yoshimi ^{[1
]}

Nagase, Reina ^{[1
]}

Kashimoto, Yoshinori ^{[2
]}

Suzuki, Makoto ^{[2
]}

Schulte, Nina ^{[5
]}

Polier, Gernot ^{[5
]}

Kurimoto, Akiko ^{[1
]}

Tomoe, Yumiko ^{[1
]}

Toyota, Akiko ^{[1
]}

Yoneyama, Tomoko ^{[2
]}

Imai, Emi ^{[2
]}

Watanabe, Kenji ^{[1
]}

Hamada, Tomoaki ^{[1
]}

Kanada, Ryutaro ^{[1
]}

Watanabe, Jun ^{[1
]}

Kagoshima, Yoshiko ^{[1
]}

Tokumaru, Eri ^{[1
]}

Murata, Kenji ^{[1
]}

Baba, Takayuki ^{[1
]}

Shinozaki, Taeko ^{[1
]}

Ohtsuka, Masami ^{[1
]}

Goto, Koichi ^{[1
]}

Karibe, Tsuyoshi ^{[1
]}

Deguchi, Takao ^{[6
]}

Gocho, Yoshihiro ^{[6
]}

Yoshida, Masanori ^{[3
]}

Tomizawa, Daisuke ^{[6
]}

Kato, Motohiro ^{[3
,4
,6
]}

Tsutsumi, Shinji ^{[1
]}

Kitagawa, Mayumi ^{[1
]}

Abe, Yuki ^{[1
]}

机构：

[1] Daiichi Sankyo Co Ltd, Shinagawa R&D Ctr, 1-2-5 Hiromachi,Shinagawa Ku, Tokyo 1400005, Japan

[2] Daiichi Sankyo RD Novare Co Ltd, Tokyo, Japan

[3] Natl Res Inst Child Hlth & Dev, Dept Pediat Hematol & Oncol Res, Tokyo, Japan

[4] Univ Tokyo, Dept Pediat, Tokyo, Japan

[5] Daiichi Sankyo Europe GmbH, Munich, Germany

[6] Natl Ctr Child Hlth & Dev, Childrens Canc Ctr, Tokyo, Japan

来源：

CANCER CELL INTERNATIONAL | 2023年 / 23卷 / 01期

关键词：

Menin-MLL1; inhibitor; MLL1-r or NPM1c acute leukemia; Leukemia-initiating cells; STEM-CELLS; IDENTIFICATION; PROGENITOR; MODELS;

D O I：

10.1186/s12935-023-02877-y

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BackgroundMixed 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.MethodsWe evaluated the preclinical efficacy of DS-1594a as well as DS-1594a center dot HCl (the HCl salt of DS-1594a) and DS-1594a center dot 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.ResultsOur results showed that MLL1-r or NPM1c human leukemic cell lines were selectively and highly sensitive to DS-1594a center dot HCl, with 50% growth inhibition values < 30 nM. Compared with cytrabine, the standard chemotherapy drug as AML therapy, both DS-1594a center dot HCl and DS-1594a center dot 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 center dot HCl and DS-1594a center dot 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.ConclusionWe 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).

引用

页数：16

共 41 条

[41] Discovery of M-1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression [J].

Zhang, Meng ;

Aguilar, Angelo ;

Xu, Shilin ;

Huang, Liyue ;

Chinnaswamy, Krishnapriya ;

Sleger, Taryn ;

Wang, Bo ;

Gross, Stefan ;

Nicolay, Brandon N. ;

Ronseaux, Sebastien ;

Harvey, Kaitlin ;

Wang, Yu ;

McEachern, Donna ;

Kirchhoff, Paul D. ;

Liu, Zhaomin ;

Stuckey, Jeanne ;

Tron, Adriana E. ;

Liu, Tao ;

Wang, Shaomeng .

JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (14) :10333-10349

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