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基于片段方法和核磁共振引导优化的PRC1抑制剂的开发

Development of PRC1 Inhibitors Employing Fragment-Based Approach and NMR-Guided Optimization.

作者信息

Yao Yiwu, Simes Miranda L, Ying Weijiang, Zhao Qingjie, Winkler Alyssa, Shukla Shirish, Gray Felicia, Nikolaidis Caroline, Hewett Geoff, Grembecka Jolanta, Cierpicki Tomasz

机构信息

Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.

出版信息

J Med Chem. 2025 Jan 23;68(2):1382-1396. doi: 10.1021/acs.jmedchem.4c01955. Epub 2025 Jan 2.

DOI:10.1021/acs.jmedchem.4c01955
PMID:39746899
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11969575/
Abstract

Polycomb Repressive Complex 1 (PRC1) is associated with transcriptional silencing, and its dysregulation plays an important role in various cancers. Well-characterized PRC1 inhibitors can facilitate the exploration of PRC1 inhibition as therapeutic agents. By employing an NMR-based fragment screening approach, we have previously identified a very weak millimolar ligand , which directly binds to RING1B-BMI1. Then, we reported a low-micromolar PRC1 inhibitor, , which is active in leukemic cells, showing inhibition of H2A ubiquitylation and modulation of target genes. Here, we describe details of the optimization campaign of into potent PRC1 inhibitors by guiding the SAR employing two NMR approaches and a probe-based biochemical assay. These efforts, combined with medicinal chemistry optimization, resulted in the development of and slightly improved . We have demonstrated that binds to both RING1A and RING1B proteins and inhibits the activity of RING1B-BMI1 and RING1B-PCGF1, representing both canonical and noncanonical PRC1 complexes.

摘要

多梳抑制复合物1（PRC1）与转录沉默相关，其失调在多种癌症中起重要作用。特征明确的PRC1抑制剂有助于探索PRC1抑制作为治疗药物的可能性。通过采用基于核磁共振的片段筛选方法，我们之前鉴定出一种非常弱的毫摩尔级配体，它直接与RING1B - BMI1结合。然后，我们报道了一种低微摩尔级的PRC1抑制剂，它在白血病细胞中具有活性，显示出对H2A泛素化的抑制作用以及对靶基因的调控作用。在这里，我们描述了通过采用两种核磁共振方法和一种基于探针的生化分析来指导构效关系，将其优化为强效PRC1抑制剂的详细过程。这些努力，结合药物化学优化，促成了的开发以及的略微改进。我们已经证明，能与RING1A和RING1B蛋白结合，并抑制RING1B - BMI1和RING1B - PCGF1的活性，代表了经典和非经典的PRC1复合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/47e5cda71455/nihms-2065895-f0024.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/de960f74a1b2/nihms-2065895-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/79b652d596d8/nihms-2065895-f0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/cc5f9d43b947/nihms-2065895-f0017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/c62388dde18f/nihms-2065895-f0018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/1e552d40ba1e/nihms-2065895-f0019.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/fa837480823f/nihms-2065895-f0020.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/8eca338558c3/nihms-2065895-f0021.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/aa2eb5688f1e/nihms-2065895-f0022.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/10b4493cb033/nihms-2065895-f0023.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/47e5cda71455/nihms-2065895-f0024.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/de960f74a1b2/nihms-2065895-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/79b652d596d8/nihms-2065895-f0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/cc5f9d43b947/nihms-2065895-f0017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/c62388dde18f/nihms-2065895-f0018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/1e552d40ba1e/nihms-2065895-f0019.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/fa837480823f/nihms-2065895-f0020.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/8eca338558c3/nihms-2065895-f0021.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/aa2eb5688f1e/nihms-2065895-f0022.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/10b4493cb033/nihms-2065895-f0023.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0725/11969575/47e5cda71455/nihms-2065895-f0024.jpg

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