Discovery and characterization of a selective p300 degrader reveals deep anti‑tumor activity in CBP mutant cancers

Paralogous protein pairs harboring loss-of-function mutations in one member have emerged as a promising opportunity in precision oncology, owing to their well-defined mechanistic complementarity. Among these, CBP and p300 are acetyltransferase paralogs whose functional redundancy has been exploited in genomic screens revealing synthetic lethality in CBP-deficient cancers when p300 is targeted. However, efforts to develop p300‑specific inhibitors have been hampered by high sequence homology within functional domains, while dual p300/CBP inhibitors have faced on‑target hematologic toxicities from simultaneous inhibition of both paralogs. Here, the discovery of potent, selective p300 degraders that exhibit robust efficacy across multiple CBP loss-of-function (LoF) cancer models is reported.Efforts at SKLSL led to the discovery of an optimized heterobifunctional degrader that induces rapid and selective p300 degradation (DC₉₀ < 10 nM, Dmax >90%) within 2 hours, with no detectable CBP degradation up to 48 h (DC₅₀ > 10 µM). Mechanistic studies confirmed an on-target mode of action, with complete loss of H3K27 acetylation observed in CBP knockout (KO) H1299 cells (IC₅₀ < 0.5 nM, Max Inh > 97%), while p300 KO and wild-type cells remained unaffected (IC₅₀ > 10 µM). Correspondingly, growth inhibition was restricted to CBP KO cells (gIC₅₀ < 5 nM), confirming p300 dependence.To support these findings, computational analysis was performed to identify endogenous cell lines with putative CBP loss-of-function (LoF) mutations across a range of cancer types, including bladder cancer, SCLC, DLBCL, and CRC. CBP LoF cell lines exhibited strong sensitivity to p300 degradation, with a median gIC₅₀ ≤ 1 nM (n = 19), while CBP wild-type and non-LoF mutant lines remained largely unresponsive (median gIC₅₀ > 10 µM, n = 15). Importantly, the observed growth inhibition in CBP LoF lines closely correlated with robust suppression of H3K27 acetylation and downregulation of c-Myc, reinforcing the on-target mechanism of action. These in vitro results translated into striking in vivo efficacy: once-daily oral dosing of the p300 degrader (30 mpk) led to near-complete p300 degradation in tumors and marked tumor regression (TR) across xenograft models, including SW780 (TR = 82%, bladder cancer), NCI-H1876 (TR = 100%, SCLC), PFIEFFER (TR = 98%, DLBCL), and KARPAS422 (TR = 20%, DLBCL).Furthermore, bone marrow colony-forming assays demonstrated a markedly improved safety profile, with the p300-selective degrader showing minimal hematologic toxicity (IC₅₀ >10 µM) compared to a clinical stage dual p300/CBP inhibitor (IC₅₀ = 121 nM) or dual degrader (IC₅₀ = 16 nM).Collectively, these results establish selective p300 degradation as a powerful therapeutic strategy for CBP loss-of-function cancers, offering robust anti-tumor activity and a significantly enhanced therapeutic index relative to dual inhibition.