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 3.0x 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 5x stress, and 30 at extreme 10x 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.