Tinghu Zhang

Abstract TP53 is the most commonly mutated gene in cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here the discovery and characterization of a small molecule chemical inducer of proximity that activates mutant p53. We named this compound TRanscriptional Activator of p53 (TRAP-1) due to its ability to engage p53Y220C and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription.

Highlights • Inhibitor THZ-P1-2 shows PI5P4K enzyme inhibition and target engagement in cells • THZ-P1-2 covalently targets unannotated cysteines outside the PI5P4K active site • AML/ALL cell lines are broadly sensitive to THZ-P1-2's covalent effects • PI5P4K inhibition causes autophagy disruption and upregulates TFEB signaling Summary The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases.

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