Discovery and characterization of a selective p300 degrader reveals broad anti‑tumor activity in p300‑dependent cancers

p300 and CBP are paralogous lysine acetyltransferases with both shared and distinct roles in cancer. p300 acts as a key transcriptional co‑activator in tumors driven by lineage‑ or tumor‑specific gene programs, such as AR⁺ prostate and hematologic cancers. While efforts to develop p300‑specific inhibitors have been hindered by high sequence homology with CBP, dual p300/CBP inhibitors have shown limited clinical progress due to on‑target hematologic toxicity resulting directly from simultaneous inhibition of both paralogs. Here, the discovery of a selective p300 degrader with potent activity in castration‑resistant prostate cancer and multiple myeloma, where p300 is essential for oncogenic signaling, reported.[LJ1] Efforts at SKLSL led to the discovery of [SK2] an optimized heterobifunctional degrader that exhibits rapid and selective p300 degradation (DC₉₀ < 10 nM, Dmax > 90%) within 2 hours and no CBP degradation up to 48 h (DC₅₀ > 10 µM). Mechanistic studies confirm an on-target effect, with complete loss of H3K27 acetylation in CBP knockout (KO) H1299 cells (IC₅₀ < 0.5 nM, Max Inh > 97%), while p300 KO and wild-type cells remain unaffected (IC₅₀ > 10 µM). Across a panel of prostate cancer lines, p300 degradation caused robust growth suppression in AR⁺ cells and downregulation of c‑Myc and AR, key transcriptional drivers of tumorigenesis. In a panel of multiple myeloma cell lines, p300 degraders displayed superior potency compared with dual p300/CBP inhibitors and pomalidomide. Importantly, these in vitro findings translated into efficacy in vivo . Once-daily oral administration at 30 mpk in xenograft models led to near-complete tumor p300 degradation and strong anti-tumor efficacy, with tumor growth inhibition (TGI) of 100% (VCaP, AR⁺ CRPC), 77% (LNCaP, AR⁺ CRPC), and 86% (OPM2, multiple myeloma).Furthermore, bone marrow colony‑forming assays revealed a significantly improved safety margin (IC₅₀ > 10 µM) relative to a dual p300/CBP inhibitor (IC₅₀ = 121 nM) and a dual degrader (IC₅₀ = 16 nM), supporting an enhanced therapeutic index.Collectively, these findings establish that selective p300 degradation delivers potent anti‑tumor efficacy while minimizing hematologic toxicity, offering a promising therapeutic approach for p300‑dependent cancers driven by either lineage‑specific or tumor‑intrinsic p300 essentiality.