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Ref Type Journal Article
PMID (41748563)
Authors Mavridi D, Funk JS, Balourdas DI, Krämer A, Khan Tareque R, Timofeev O, Spencer J, Stiewe T, Joerger AC
Title Targeting the p53 cancer mutants Y220C, Y220N, and Y220S with the small-molecule stabilizer rezatapopt.
Journal Vol Issue Date Pages Journal Short Title
Cell death & disease 17 1 2026 Feb 26 Cell Death Dis
URL
Abstract Text The cavity-creating p53 cancer mutation Y220C, which accounts for an estimated 125,000 new cancer cases per year, serves as an excellent paradigm for the development of mutant p53 reactivators. Several molecules that reactivate this thermolabile cancer mutant by targeting the mutation-induced crevice have been developed, and one of them, rezatapopt, is currently in clinical trials. The less frequently occurring Y220N and Y220S mutations are even more destabilizing than Y220C but create a similar surface crevice, raising the question of whether cancer patients with these mutations might also benefit from rezatapopt treatment. Here, we show that rezatapopt also binds to the Y220N and Y220S mutants, with nanomolar affinity, resulting in a full recovery of wild-type-like stability for the latter. High-resolution crystal structures of all three mutants bound to rezatapopt revealed a conserved binding mode, highlighting key interactions, including multipolar interactions of a fluorine substituent at a chiral center with the protein backbone. Consistent with the biophysical and structural data, rezatapopt reactivated p53 signaling in both Y220C and Y220S mutant cells by restoring the folded conformation and transcriptional activity, leading to anti-proliferative effects and apoptosis, albeit requiring higher compound concentrations in Y220S cells. The Y220N mutant, despite exhibiting high-nanomolar affinity for rezatapopt and substantial stabilization, did not show noticeable effects in cells at the concentrations tested, as rezatapopt binding resulted in only partial compensation for the mutation-induced loss of stability, for which we provide a structural explanation. Our data suggest that the development of clinical pan-Y220C/N/S reactivators, which could benefit an additional 10,000 patients per year, is challenging but not impossible.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 Y220S Advanced Solid Tumor decreased response Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, Rezatapopt (PC14586) reactivated Tp53 function, inhibited proliferation, viability and colony formation, and induced cell cycle arrest and apoptosis in cells expressing TP53 Y220S with reduced potency compared to TP53 Y220C in culture (PMID: 41748563). 41748563
TP53 Y220N Advanced Solid Tumor no benefit Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, Rezatapopt (PC14586) partially stabilized Tp53 protein and marginally inhibited proliferation, but did not inhibit viability and colony formation, and did not induce apoptosis in cells expressing TP53 Y220N in culture (PMID: 41748563). 41748563
TP53 Y220H Advanced Solid Tumor no benefit Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, Rezatapopt (PC14586) did not inhibit proliferation, viability, and colony formation, and did not induce apoptosis in cells expressing TP53 Y220H in culture (PMID: 41748563). 41748563
TP53 Y220C Advanced Solid Tumor sensitive Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, Rezatapopt (PC14586) reactivated Tp53 function, inhibited proliferation, viability and colony formation, and induced cell cycle arrest and apoptosis in cells expressing TP53 Y220C in culture (PMID: 41748563). 41748563