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发现一种髓系细胞白血病 1（Mcl-1）抑制剂，在血液系统和实体肿瘤的小鼠模型中表现出强大的活性。

Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent Activities in Mouse Models of Hematological and Solid Tumors.

机构信息

Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.

Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120 Vienna, Austria.

出版信息

J Med Chem. 2024 Aug 22;67(16):14370-14393. doi: 10.1021/acs.jmedchem.4c01188. Epub 2024 Aug 5.

DOI:10.1021/acs.jmedchem.4c01188
PMID:39102508
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11345828/
Abstract

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound , that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.

摘要

髓样细胞白血病 1（Mcl-1）是内在凋亡途径的关键调节因子。Mcl-1 的过表达与高肿瘤分级、不良预后以及内在和获得性癌症治疗耐药性相关。在此，我们公开了一种小分子 Mcl-1 抑制剂化合物的结构导向设计，该化合物与 Mcl-1 的结合具有亚纳摩尔亲和力，在细胞培养测定中抑制生长，并且在小鼠和犬药代动力学（PK）实验中清除率低。在 Mcl-1 敏感的血液学和实体肿瘤异种移植模型中作为单一药物进行评估，结果导致肿瘤消退。Mcl-1 敏感和 Mcl-1 不敏感肺癌衍生异种移植分别与 和多西他赛或拓扑替康联合治疗，导致肿瘤反应增强。这些发现支持这样一个前提，即其他疗法通过促凋亡引发肿瘤细胞，再联合 Mcl-1 抑制，可能会显著扩大 Mcl-1 抑制剂可能有益的癌症亚类。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28b/11345828/6c046631c0d3/jm4c01188_0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28b/11345828/22e1ea6b9517/jm4c01188_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28b/11345828/496161ce5977/jm4c01188_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28b/11345828/895a3890c3bc/jm4c01188_0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28b/11345828/6c046631c0d3/jm4c01188_0009.jpg

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3
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5
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