Biology subjects

Sims, R. J.

Publications and source records attributed to Sims, R. J..

3 recordsLinked to original sources

bioRxiv2026

Thermodynamic Insights into the WT and Y220C TP53 DBDs Reveals that the Oncogenic Y220C Variant is a Loss of Function Mutation for Zn2+-binding at Physiological Temperature

We present evidence of previously unrecognized allosteric connectivity across the TP53 DNA binding domain (DBD). Specifically, we have found evidence of explicit influence on the Zn2+-binding site from the region surrounding the hotspot Y220C mutation. This allosteric connectivity is intertwined with a temperature-dependent destabilization of Zn2+ binding in both the WT and Y220C DBDs. Our studies indicate that the Y220C mutation exacerbates this temperature-dependent destabilization of Zn2+-binding to result in overall destabilization of the Y220C variant. We provide detailed thermodynamic evidence that Rezatapopt, a small molecule reactivator of the Y220C DBD, engages Y220C through two distinct thermodynamic pathways and restores WT-level Zn2+-affinity to this oncogenic variant. A series of thermodynamic models describing the WT and Y220C conformational landscapes, as well as the Rezatapopt binding mechanisms, are proposed.

biochemistry↗

bioRxiv2025

Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

We report our mechanistic investigation into the conformationally-driven activation bias of PPARG in muscle-invasive urothelial cancer (MIUC) and our efforts to pharmacologically reverse this activation bias through covalent PPARG inverse agonism. We utilized studies into tumor-associated mutations in both PPARG and RXRA, as well as a combination of structure-based drug design merged with insights from biochemical mechanistic studies to discover FX-909, a first-in-class clinical PPARG inverse agonist that robustly enforces a conformationally repressive state of PPARG, even in highly activated contexts such as RXRA S427F mutation and PPARG amplification. FX-909 is a potent, highly selective, and powerful suppressor of PPARG transcriptional activity through enhancement of PPARG nuclear corepressor binding (NCOR) affinity. Treatment with FX-909 resulted in selective growth inhibition in PPARG-activated MIUC cell lines. Further, FX-909 achieved durable regressions in xenograft models of MIUC through inverse agonism of PPARG. FX-909 is the first chemical tool available to the community that is capable of recapitulating PPARG genetic knockout in vivo and is currently in clinical development for the treatment of intractable MIUC.

cancer biology↗

bioRxiv2021

CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells

Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.

cancer biology↗