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发现一种强效、选择性且具有细胞活性的 SPIN1 抑制剂。

Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor.

机构信息

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Department of Urology and Center for Clinical Research, University Freiburg Medical Center, Freiburg 79106, Germany.

出版信息

J Med Chem. 2024 Apr 11;67(7):5837-5853. doi: 10.1021/acs.jmedchem.4c00121. Epub 2024 Mar 27.

DOI:10.1021/acs.jmedchem.4c00121
PMID:38533580
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11022035/
Abstract

The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure-activity relationship study that led to the discovery of compound , a dual SPIN1 and G9a/GLP inhibitor, and compound (MS8535), a SPIN1 selective inhibitor. We solved the cocrystal structure of SPIN1 in complex with , confirming that occupied one of the three Tudor domains. Importantly, displayed high selectivity for SPIN1 over 38 epigenetic targets, including G9a/GLP, and concentration dependently disrupted the interactions of SPIN1 and H3 in cells. Furthermore, was bioavailable in mice. We also developed (MS8535N), which was inactive against SPIN1, as a negative control of . Collectively, these compounds are useful chemical tools to study biological functions of SPIN1.

摘要

甲基赖氨酸读取蛋白 SPIN1 在各种人类疾病中发挥着重要作用。然而，靶向甲基赖氨酸读取蛋白一直具有挑战性。很少有细胞活性的 SPIN1 抑制剂被开发出来。我们之前曾报道过，我们的 G9a/GLP 抑制剂 UNC0638 弱抑制 SPIN1。在这里，我们展示了我们全面的结构活性关系研究，该研究导致发现了双重 SPIN1 和 G9a/GLP 抑制剂化合物 ，以及 SPIN1 选择性抑制剂化合物 (MS8535)。我们解析了 SPIN1 与 形成复合物的共晶结构，证实 占据了三个 Tudor 结构域之一。重要的是， 对 38 种表观遗传靶标（包括 G9a/GLP）具有高选择性，并且在细胞中浓度依赖性地破坏了 SPIN1 和 H3 的相互作用。此外， 在小鼠中具有生物利用度。我们还开发了针对 SPIN1 无活性的化合物 (MS8535N)，作为 的阴性对照。总之，这些化合物是研究 SPIN1 生物学功能的有用化学工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/606e37a38e39/nihms-1981086-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/b223c5077730/nihms-1981086-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/2d0d45fd098e/nihms-1981086-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/cafdfed6cde1/nihms-1981086-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/b446092b8e83/nihms-1981086-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/f95371bb151e/nihms-1981086-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/a8d76ca5ce40/nihms-1981086-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/f2e9c91bf85b/nihms-1981086-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/e3168cd9bcb1/nihms-1981086-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/7549b54f6dec/nihms-1981086-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/a88bce754307/nihms-1981086-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/6101d7e27dcb/nihms-1981086-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/784978bf84b2/nihms-1981086-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/699ae1f3a2a3/nihms-1981086-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/606e37a38e39/nihms-1981086-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/b223c5077730/nihms-1981086-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/2d0d45fd098e/nihms-1981086-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/cafdfed6cde1/nihms-1981086-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/b446092b8e83/nihms-1981086-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/f95371bb151e/nihms-1981086-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/a8d76ca5ce40/nihms-1981086-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/f2e9c91bf85b/nihms-1981086-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/e3168cd9bcb1/nihms-1981086-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/7549b54f6dec/nihms-1981086-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/a88bce754307/nihms-1981086-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/6101d7e27dcb/nihms-1981086-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/784978bf84b2/nihms-1981086-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/699ae1f3a2a3/nihms-1981086-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2978/11022035/606e37a38e39/nihms-1981086-f0015.jpg

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本文引用的文献

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Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors.基于结构的A366衍生物作为Spindlin1抑制剂的设计、对接及结合自由能计算
Int J Mol Sci. 2021 May 31;22(11):5910. doi: 10.3390/ijms22115910.
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Structural mechanism of bivalent histone H3K4me3K9me3 recognition by the Spindlin1/C11orf84 complex in rRNA transcription activation.
Spindlin1/C11orf84 复合物识别二价组蛋白 H3K4me3K9me3 的结构机制在 rRNA 转录激活中的作用。
Nat Commun. 2021 Feb 11;12(1):949. doi: 10.1038/s41467-021-21236-x.
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Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease.表观遗传学及其他：以蛋白质赖氨酸甲基化写作者为靶点治疗疾病。
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SPIN1 triggers abnormal lipid metabolism and enhances tumor growth in liver cancer.SPIN1 触发异常脂质代谢并增强肝癌中的肿瘤生长。
Cancer Lett. 2020 Feb 1;470:54-63. doi: 10.1016/j.canlet.2019.11.032. Epub 2019 Nov 29.
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A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function.一种用于研究染色质功能的结构域蛋白 Spindlin1 的化学探针。
J Med Chem. 2019 Oct 24;62(20):9008-9025. doi: 10.1021/acs.jmedchem.9b00562. Epub 2019 Oct 15.
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Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1).发现一种强效且选择性的赖氨酸甲基化读蛋白 Spindlin 1（SPIN1）的片段类似物抑制剂。
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Nat Commun. 2019 Jan 3;10(1):19. doi: 10.1038/s41467-018-07905-4.
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