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A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9960487/ https://www.ncbi.nlm.nih.gov/pubmed/36841758 http://dx.doi.org/10.1186/s12935-023-02877-y |
_version_ | 1784895525289459712 |
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author | 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 |
author_facet | 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 |
author_sort | Numata, Masashi |
collection | PubMed |
description | 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). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-023-02877-y. |
format | Online Article Text |
id | pubmed-9960487 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-99604872023-02-26 A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1 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 Int Research 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). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-023-02877-y. BioMed Central 2023-02-25 /pmc/articles/PMC9960487/ /pubmed/36841758 http://dx.doi.org/10.1186/s12935-023-02877-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research 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 A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1 |
title | A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1 |
title_full | A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1 |
title_fullStr | A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1 |
title_full_unstemmed | A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1 |
title_short | A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1 |
title_sort | novel menin-mll1 inhibitor, ds-1594a, prevents the progression of acute leukemia with rearranged mll1 or mutated npm1 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9960487/ https://www.ncbi.nlm.nih.gov/pubmed/36841758 http://dx.doi.org/10.1186/s12935-023-02877-y |
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