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一盒化学物质抑制 MEN1 肿瘤抑制基因促进白血病。

A Box of Chemistry to Inhibit the MEN1 Tumor Suppressor Gene Promoting Leukemia.

机构信息

German Cancer Consortium (DKTK) partner site Freiburg German Cancer Research Center (DKFZ) Medical Center-University of Freiburg, Department of Urology, Breisacherstrasse 66, 79016, Freiburg, Germany.

出版信息

ChemMedChem. 2021 May 6;16(9):1391-1402. doi: 10.1002/cmdc.202000972. Epub 2021 Mar 10.

DOI:10.1002/cmdc.202000972
PMID:33534953
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8252030/
Abstract

Targeting protein-protein interactions (PPIs) with small-molecule inhibitors has become a hotbed of modern drug development. In this review, we describe a new class of PPI inhibitors that block menin from binding to MLL proteins. Menin is encoded by the MEN1 tumor suppressor, but acts as an essential cofactor for MLL/KMT2A-rearranged leukemias. The most promising menin-MLL inhibitors belong to the thienopyrimidine class and have recently entered phase I/II clinical trials for treating acute leukemias characterized by MLL/KMT2A translocations or NPM1 mutations. As single agents, thienopyrimidine compounds eradicate leukemia in a xenograft models of primary leukemic cells belonging to the MLL-rearranged or NPM1-mutant subtypes. These compounds are well tolerated with few or no side effects, which is remarkable given the tumor-suppressor function of menin. The menin-MLL inhibitors highlight how leukemia patients could benefit from a targeted epigenetic therapy with novel PPI inhibitors obtained by directed chemical evolution.

摘要

靶向蛋白质-蛋白质相互作用（PPIs）的小分子抑制剂已成为现代药物开发的热点。在这篇综述中，我们描述了一类新型的 PPI 抑制剂，它能阻止 Menin 与 MLL 蛋白结合。Menin 由 MEN1 肿瘤抑制基因编码，但作为 MLL/KMT2A 重排白血病的必需辅助因子发挥作用。最有前途的 Menin-MLL 抑制剂属于噻吩嘧啶类，最近已进入 I/II 期临床试验，用于治疗以 MLL/KMT2A 易位或 NPM1 突变为特征的急性白血病。作为单一药物，噻吩嘧啶化合物在属于 MLL 重排或 NPM1 突变亚型的原代白血病细胞的异种移植模型中能根除白血病。这些化合物具有良好的耐受性，几乎没有或没有副作用，这在 Menin 的肿瘤抑制功能下是显著的。Menin-MLL 抑制剂强调了如何通过定向化学进化获得新型 PPI 抑制剂的靶向表观遗传疗法，使白血病患者受益。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/d6a20c3c4476/CMDC-16-1391-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/2b9d01886f24/CMDC-16-1391-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/2f6a1ad2eceb/CMDC-16-1391-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/74814a01df7b/CMDC-16-1391-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/eaaf6864d378/CMDC-16-1391-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/d6a20c3c4476/CMDC-16-1391-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/2b9d01886f24/CMDC-16-1391-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/2f6a1ad2eceb/CMDC-16-1391-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/74814a01df7b/CMDC-16-1391-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/eaaf6864d378/CMDC-16-1391-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d0c/8252030/d6a20c3c4476/CMDC-16-1391-g001.jpg

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Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong Antitumor Activity.发现 M-808 是一种强效、共价的小分子 Menin-MLL 相互作用抑制剂，具有很强的抗肿瘤活性。
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The molecular functions of common and atypical MLL fusion protein complexes.
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A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1.一种新型的Menin-MLL1抑制剂DS-1594a可阻止伴有MLL1重排或NPM1突变的急性白血病进展。
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