Abstract 5177: Exceptionally selective and orally bioavailable p300 degraders for the treatment of CBP-mutant and p300-dependent cancers

Abstract EP300 (or p300) acts as histone acetyltransferase (HAT) and transcriptional adapter or co-activator regulating transcription via chromatin remodelling. Both histone and non-histone proteins are acetylated by p300. p300 functions by scaffolding or as a co-activator and enhancer of different transcription factors like HIF1a, BRCA-1, p53, NFκB, c-Myc, estrogen receptor (ER) and androgen receptor (AR) as well as other proteins such as PD-L1 and FOXP3. Selective targeting of p300 is expected to lead to therapeutic efficacy in CBP-mutant and p300-dependent malignancies with high degree of tolerability as a result of sparing the other paralog CBP in normal cells. CBP mutant cancers comprise of several solid and haematological malignancies such as bladder, lung, colorectal, melanoma, DLBCL, MM etc. and p300-dependent malignancies include prostate cancer, in which p300 plays a major role for androgen-dependent and independent transactivation of the AR, MYCN-amplified neuroblastoma and ER+ breast cancers. Conventional CBP/p300 BD inhibitors lack paralog selectivity due to high sequence homology, leading to adverse effects like severe thrombocytopenia in clinical settings. We have adopted a degrader approach to solve this selectivity challenge by means of a differentiated ternary complex. Herein, we report first-in-class highly potent and paralog selective p300 degraders with excellent selectivity over CBP along with other bromodomain containing proteins such as BRD4 and CRBN neosubstrates such as GSPT1. These degraders induce synthetic lethality in CBP loss-of-function mutant cell lines by selectively degrading p300 and demonstrate strong antiproliferative effects across CBP-mutant and p300-dependent models, including AR-positive prostate cancer. Identified p300 selective degraders exhibited good oral bioavailability and were well tolerated in rodents without showing thrombocytopenia. Demonstration of efficacy in CBP mutant and AR-positive CDX models is underway and will be presented subsequently. In summary, we have identified highly selective degraders of p300 with desirable profile. Efforts are in progress towards nominating a development candidate by Q1 2026. Citation Format: Iram Khan Iqbal, Krishna Chaitanya T, Kishore Narayanan, Naveen Kumar R, Aravind A. B, Avinash Kumar, Dabbeeru Madhu Babu, Pathur Obanna, Ankita Manna, Rabin Madhaiyan, Damodhran B, Shraddha B Shirsat, Shilpa S Nayak, Suraj T Gore, Mohamad Fairus, Girish Daginakatte, Rajesh Eswarappa, Chandrasekhar Abbineni, Saravanan Thiyagarajan, Murali Ramachandra, Susanta Samajdar. Exceptionally selective and orally bioavailable p300 degraders for the treatment of CBP-mutant and 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 5177.