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用于三阴性乳腺癌治疗的小分子Mcl-1抑制剂。

Small molecule Mcl-1 inhibitor for triple negative breast cancer therapy.

作者信息

Dong Shengli, Alahari Suresh K

机构信息

TYK Medicines, Inc., Zhejiang, China.

Department of Biochemistry and Molecular Biology, LSHSC School of Medicine, New Orleans, LA, United States.

出版信息

Front Cell Dev Biol. 2024 Sep 20;12:1408107. doi: 10.3389/fcell.2024.1408107. eCollection 2024.

DOI:10.3389/fcell.2024.1408107
PMID:39372954
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11449857/
Abstract

Apoptosis is an evolutionarily conserved cell death pathway that plays a crucial role in maintaining tissue homeostasis, orchestrating organismal development, and eliminating damaged cells. Dysregulation of apoptosis can contribute to the pathogenesis of malignant tumors and neurodegenerative diseases. Anticancer drugs typically possess the capacity to induce apoptosis in tumor cells. The Bcl-2 protein family, consisting of 27 members in humans, serves as the key regulator of mitochondrial function. This family can be divided into two functional groups: anti-apoptotic proteins (e.g., Bcl-2, Bcl-xl, Mcl-1) and pro-apoptotic proteins (e.g., Bad, Bax). Mcl-1 exerts its function by binding pro-apoptotic Bcl-2 proteins thereby preventing apoptosis induction. Overexpression of Mcl-1 not only correlates closely with tumorigenesis but also associates significantly with resistance towards targeted therapy and conventional chemotherapy. Effective induction of apoptosis can be achieved through inhibition or interference with Mcl-1. Thus, this mini review discusses existing Mcl-1 inhibitors.

摘要

细胞凋亡是一种进化上保守的细胞死亡途径,在维持组织稳态、协调机体发育以及清除受损细胞方面发挥着关键作用。细胞凋亡失调可导致恶性肿瘤和神经退行性疾病的发病机制。抗癌药物通常具有诱导肿瘤细胞凋亡的能力。人类的Bcl-2蛋白家族由27个成员组成,是线粒体功能的关键调节因子。该家族可分为两个功能组:抗凋亡蛋白(如Bcl-2、Bcl-xl、Mcl-1)和促凋亡蛋白(如Bad、Bax)。Mcl-1通过结合促凋亡Bcl-2蛋白发挥其功能,从而防止细胞凋亡的诱导。Mcl-1的过表达不仅与肿瘤发生密切相关,还与对靶向治疗和传统化疗的耐药性显著相关。通过抑制或干扰Mcl-1可以有效诱导细胞凋亡。因此,本综述讨论了现有的Mcl-1抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e6e/11449857/1fc59a408f61/fcell-12-1408107-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e6e/11449857/ec9296db4f08/fcell-12-1408107-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e6e/11449857/1fc59a408f61/fcell-12-1408107-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e6e/11449857/ec9296db4f08/fcell-12-1408107-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e6e/11449857/1fc59a408f61/fcell-12-1408107-g002.jpg

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本文引用的文献

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Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions.靶向癌症治疗中的髓样白血病-1:进展与方向。
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Targeting MCL-1 protein to treat cancer: opportunities and challenges.靶向MCL-1蛋白治疗癌症:机遇与挑战。
Front Oncol. 2023 Jul 31;13:1226289. doi: 10.3389/fonc.2023.1226289. eCollection 2023.
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Targeting Mcl-1 by a small molecule NSC260594 for triple-negative breast cancer therapy.小分子 NSC260594 靶向 Mcl-1 治疗三阴性乳腺癌。
Sci Rep. 2023 Jul 22;13(1):11843. doi: 10.1038/s41598-023-37058-4.
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Venetoclax resistance: mechanistic insights and future strategies.维奈托克耐药性:机制见解与未来策略
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PROTAC targeted protein degraders: the past is prologue.PROTAC 靶向蛋白降解剂:过去是序幕。
Nat Rev Drug Discov. 2022 Mar;21(3):181-200. doi: 10.1038/s41573-021-00371-6. Epub 2022 Jan 18.
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Sacituzumab Govitecan for Treatment of Refractory Triple-Negative Metastatic Breast Cancer.戈沙妥珠单抗治疗难治性三阴性转移性乳腺癌
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Kinase drug discovery 20 years after imatinib: progress and future directions.伊马替尼发现 20 年后的激酶药物研发:进展与未来方向
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8
Targeting MCL-1 in cancer: current status and perspectives.靶向 MCL-1 在癌症中的治疗:现状与展望。
J Hematol Oncol. 2021 Apr 21;14(1):67. doi: 10.1186/s13045-021-01079-1.
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G-quadruplexes: a promising target for cancer therapy.四链体:癌症治疗的有前景靶点。
Mol Cancer. 2021 Feb 25;20(1):40. doi: 10.1186/s12943-021-01328-4.
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Cancer Statistics, 2021.癌症统计数据,2021.
CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12.