Abstract LB237: p300-selective degraders illustrate potent anti-tumor activity in a distinct subset of cancers

Abstract p300/CBP are paralog lysine acetyltransferases known to regulate gene expression in part through their histone acetylation functions. Although these enzymes serve both overlapping and distinct normal functions, they may possess disparate roles in cancer initiation and progression. p300 plays a critical role, serving as a known regulatory cofactor in cancer subtypes with a high reliance on lineage-specific gene expression, as well as a desirable target in CBP-deficient cancers. Here we show that targeted p300-selective degraders demonstrate efficacy across several indications, including castrate-resistant prostate cancer and multiple solid tumor malignancies harboring synthetic lethal CBP mutations.We discovered potent heterobifunctional degraders with clear selectivity for p300, exhibiting near complete degradation of p300 within 2 hours (DC90 < 1nM, Dmax > 90%) and no observable degradation of CBP through 48 h (DC50 >10µM). Downstream pharmacology confirmed an on-target mechanism, with a rapid abrogation of H3K27 acetylation seen in CBP KO H1299 cells (IC50 < 0.5nM, MaxInh >97%), with essentially unperturbed H3K27Ac in p300 KO (IC50 > 10µM) or parental wild-type cells (IC50 > 2µM). Furthermore, we observed potent growth inhibition only in H1299 CBP KO cells (gIC50 < 5nM) whereas growth of p300 KO or parental wild-type cells was minimally impacted (gIC50 > 10µM). We tested our degraders across a panel of prostate cancer lines, where we found growth suppression of AR+ cells and a downregulation of c-myc as well as ARv7, two key drivers of prostate tumorigenesis. We further employed computational algorithms to define a subset of CBP alterations conferring a putative loss-of-function (LoF) phenotype and identified cell lines harboring the relevant mutations. Results in these endogenous lines recapitulated what we observed with our CBP KO cells, with potent growth inhibition seen in CBP LoF cell lines (median gIC50 < 300nM, n= 46), whereas CBP wild-type or non-LoF CBP mutant cells were largely unresponsive (median gIC50 >10µM, n = 66). To confirm the in vitro results in an in vivo setting, we evaluated the response in mice harboring LOVO (CBP LoF) or VCaP (AR+ mCRPC) xenografts. Once daily oral administration of our compound led to almost complete degradation of p300 within xenograft tumors, resulting in a pronounced inhibition of tumor growth. Lastly, we profiled p300 degradation in human bone marrow derived myeloid progenitor colony-forming assays where we observed a significant reduction in toxicity (IC50 = 4µM) compared to a dual CBP/p300 inhibitor (IC50 = 121nM) or degrader (IC50 = 16nM), supporting the hypothesis that a p300-specific mechanism will offer an improved therapeutic index while maintaining anti-tumor efficacy.Taken together, these results underscore the therapeutic potential of a selective p300 degrader in both castrate-resistant prostate and CBP LoF cancers. SK Life Science Labs Proprietary / Confidential Citation Format: Mike R. Russell, Harshil Dhruv, Xuqing Zhang, Jeremy Roach, Nathan Kendsersky, Nelisa Bechtel, Kelsey Annen, Brian Vidal, Matt Tudor, Qiaolin Deng, Clemente Aguilar-Bonavides, Elham Behshad, Sudeep Banjade, Corey Strickland, Larry Jolivette, Helai Mohammad. p300-selective degraders illustrate potent anti-tumor activity in a distinct subset of cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB237.