Design-space requirements for abundance-amplified drug-like targeting of RHSVV/PAb240-like p53 exposure in TP53-mutant cancer

TP53-mutant cancers often accumulate p53 protein, creating a potential abundance-amplified therapeutic target, but wild-type p53 can also rise in stressed normal cells. This study defines the quantitative design requirements for an intracellular strategy targeting RHSVV/PAb240-like conformational exposure of p53 in TP53-mutant/high-p53 cancer. We integrated DepMap cell-line annotations, p53 abundance data, NCI TP53 mutation resources, and Human Protein Atlas normal-tissue immunohistochemistry, and modeled RHSVV/PAb240-like exposure as a latent design variable. Abundance-only models were compared with latent RHSVV exposure-discriminated models across target-engagement affinity, intracellular concentration, exposure ratio, output nonlinearity, and wild-type stress conditions. Abundance-only targeting was stress-fragile, with no feasible designs at or above the default 3.0× wild-type stress background. In contrast, RHSVV exposure-discriminated models retained feasible regions across the full stress sweep, requiring minimum target-to-stressed-normal exposure ratios of 3 at lower stress, 10 at 5× stress, and 30 at extreme 10× stress. Robust feasible bands required exposure ratios of 10–1000, effective Kd values of 1– 300 nM, intracellular concentration proxies of 10–1000 nM, and output sharpness of 1.0–1.25. These findings define falsifiable molecular requirements for future RHSVV/PAb240-inspired p53-state-selective therapeutic design.