Abstract 5179: Discovery and characterization of a selective p300 degrader reveals broad anti-tumor activity in p300-dependent cancers

Abstract 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. Citation Format: Harshil Dhruv, Andrew Fedoriw, Xuqing Zhang, Michael Russell, Jeremy Roach, Nathan Kendsersky, Nelisa Bechtel, Kelsey Annen, Brian Vidal, Timothy Dougherty, Clemente Aguilar-Bonavides, Elham Behshad, Sudeep Banjade, Corey Strickland, Wenxue Wu, Larry Jolivette, Helai Mohammad, Ryan Kruger. Discovery and characterization of a selective p300 degrader reveals broad anti-tumor activity in p300-dependent cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5179.