9EK5

TRIM21 PrySpry domain bound to an enhanced PRLX-93936 analog

これはPDB形式変換不可エントリーです。

9EK5 の概要

• エントリーDOI: 10.2210/pdb9ek5/pdb
• 分子名称: E3 ubiquitin-protein ligase TRIM21, (3P)-3-(4-chloro-2-ethoxyphenyl)-6-fluoro-2-[(piperazin-1-yl)methyl]quinazolin-4(3H)-one (3 entities in total)
• 機能のキーワード: trim21, ubiquitin, ubiquitin ligase, small molecule, protein degradation, innate immunity, cancer, therapeutics, immune system
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20922.86

構造登録者

Hinshaw, S.M.,Corsello, S.M.,Yuan, L.,Lu, J.,Martinez, M.,Gray, N.S. (登録日: 2024-11-30, 公開日: 2025-08-27, 最終更新日: 2026-03-11)

主引用文献

Yuan, L.,Ji, W.,Dwyer, B.G.,Lu, J.,Bian, J.,Colombo, G.M.,Martinez, M.J.,Fernandez, D.,Phillips, N.A.,Tang, M.T.,Zhou, C.W.,Quispe Calla, N.E.,Guzman Huancas, C.,Eckart, M.,Tran, J.,Jones, H.M.,Qiu, T.,Doench, J.G.,Rees, M.G.,Roth, J.A.,Cameron, M.D.,Charville, G.W.,Kuo, C.J.,Dixon, S.J.,Zhang, T.,Hinshaw, S.M.,Gray, N.S.,Corsello, S.M.
Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex.
Cancer Discov, 15:2505-2529, 2025

PubMed Abstract: Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear pore complex (NPC). Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry-based proteomics, we discovered that the clinical drug PRLX-93936 is a molecular glue that binds and reprograms the TRIM21 ubiquitin ligase to degrade the NPC. Upon compound-induced TRIM21 recruitment, the nuclear pore is ubiquitylated and degraded, resulting in the loss of short-lived cytoplasmic mRNA transcripts and the induction of cancer cell apoptosis. Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and X-ray crystallography, whereas compound-induced TRIM21-nucleoporin complex formation was demonstrated through multiple orthogonal approaches in cells and in vitro. Phenotype-guided optimization yielded compounds with 10-fold greater potency and drug-like properties, along with robust pharmacokinetics and efficacy against pancreatic cancer xenografts and patient-derived organoids.

PubMed: 40891634
DOI: 10.1158/2159-8290.CD-25-0271

実験手法

X-RAY DIFFRACTION (2.1 Å)