8PQN

NQO1 bound to RBS-10

8PQN の概要

• エントリーDOI: 10.2210/pdb8pqn/pdb
• 分子名称: NAD(P)H dehydrogenase [quinone] 1, FLAVIN-ADENINE DINUCLEOTIDE, ~{N}-[4-[(3-methylphenyl)carbonylamino]phenyl]-5-nitro-furan-2-carboxamide (3 entities in total)
• 機能のキーワード: nqo1, rbs-10, quinone reductase, degrader resistance, prodrug, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 125407.43

構造登録者

Pous, J.,Jose-Duran, F.,Mayor-Ruiz, C.,Riera, A. (登録日: 2023-07-11, 公開日: 2024-01-10, 最終更新日: 2024-03-20)

主引用文献

Barbosa, B.M.G.,Sfyaki, A.,Rafael, S.,Jose-Duran, F.,Pous, J.,Sanchez-Zarzalejo, C.,Perez-Lopez, C.,Vilanova, M.,Cigler, M.,Gay, M.,Vilaseca, M.,Winter, G.E.,Riera, A.,Mayor-Ruiz, C.
Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
Angew.Chem.Int.Ed.Engl., 63:e202316730-e202316730, 2024

PubMed Abstract: Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer.

PubMed: 38153885
DOI: 10.1002/anie.202316730

実験手法

X-RAY DIFFRACTION (3.8 Å)