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Numata, Masashi; Haginoya, Noriyasu; Shiroishi, Machiko; Hirata, Tsuyoshi; Sato-Otsubo, Aiko; Yoshikawa, Kenji; Takata, Yoshimi; Nagase, Reina; Kashimoto, Yoshinori; Suzuki, Makoto; Schulte, Nina; Polier, Gernot; Kurimoto, Akiko; Tomoe, Yumiko; Toyota, Akiko; Yoneyama, Tomoko; Imai, Emi; Watanabe, Kenji; Hamada, Tomoaki; Kanada, Ryutaro; Watanabe, Jun; Kagoshima, Yoshiko; Tokumaru, Eri; Murata, Kenji; Baba, Takayuki; Shinozaki, Taeko; Ohtsuka, Masami; Goto, Koichi; Karibe, Tsuyoshi; Deguchi, Takao; Gocho, Yoshihiro; Yoshida, Masanori; Tomizawa, Daisuke; Kato, Motohiro; Tsutsumi, Shinji; Kitagawa, Mayumi; Abe, Yuki
Cancer cell international, 02/2023, Letnik: 23, Številka: 1Journal Article
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. 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. 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. 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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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