Cisplatin-vinylsulfonamide conjugate targets PKM2 and triggers ferroptosis
- Platinum(II) complexes carrying a covalent vinylsulfonamide group were built to engage proteins beyond DNA, and competitive chemoproteomics pinpointed pyruvate kinase M2 as the direct target of lead compound Pt1.
- Binding at a cysteine pocket combines platinum ligand exchange with covalent anchoring, disrupting PKM2 oligomerization and driving nuclear translocation.
- Ferroptosis follows via a PKM2-HMOX1 axis, amplified by mitochondrial oxidative stress.
- In xenografts, antitumor activity resembled cisplatin with less liver toxicity.
💡 Points
A Pt(II) warhead plus a vinylsulfonamide is a dual-electrophile design, so selectivity worries me first: PKM2 has several reactive cysteines, and Pt itself hits glutathione and everything soft. Chemoproteomics naming one target is encouraging, but the cross-linking story needs the cysteine mutant and a Pt-free vinylsulfonamide control. Synthetically easy, mechanistically messy.
Cisplatin Conjugated with Vinylsulfonamide Cross-Links Pyruvate Kinase M2 to Trigger Ferroptosis ↗