Abstract 6065: Identification and characterization of paralogue selective CBP degraders for potential use in cancer therapy

Abstract CBP and p300 are closely related epigenetic modulators that participate in chromatin remodeling and transcription and play an oncogenic role in a variety of cancers. Studies have indicated that the selective targeting of CBP is a highly attractive therapeutic strategy for cancers with p300 mutations because of synthetic lethality, those that are dependent on Wnt/β-catenin signaling and ERα and HER2-positive breast cancers. Prevalence of high mutation frequency of p300 in several cancers including skin cancers (27%), small cell lung cancers (8%), lymphoma (8-13%) and bladder cancer (9%) further highlight an opportunity for selective inactivation of CBP in cancer therapy. However, it has not been possible to identify selective inhibitors of p300 or CBP because of the conserved sequence and structure of functional domains such as HAT domain or bromodomain. We sought to achieve selective CBP targeting by utilizing the degrader approach, which in the recent time has proven to be useful in achieving paralog selectivity due to differentiated ternary complex formation. Additionally, the degrader approach offers several inherent advantages including stronger phenotype due to greater potency, sustained action due to catalytic mode of action, overcoming resistance and greater selectivity. Utilizing a combination of structure-guided modelling and iterative medicinal chemistry strategies, we identified first-in-class selective degraders targeting CBP with varying linker lengths and compositions. Our lead compounds exhibit remarkable bias in degrading CBP in cell lines harboring loss-of-function mutations in p300, while sparing wild-type cells. Selective CBP degraders disrupted β-catenin transactivation function in a dose-dependent manner and demonstrated good oral bioavailability and PK profile in preclinical species. Further optimization of potency, selectivity, ADME properties while evaluating in vivo efficacy in appropriate models and tolerability in higher species is ongoing towards identifying a development candidate. Citation Format: Saravanan Thiyagarajan, Chandrasekhar Abbineni, Krishna Chaitanya T, Achala Apte, Iram Khan Iqbal, Naveen Kumar R, Aravind A B, Avinash Kumar, Girish A R, Aishwarya B Kamath, Deepak Dattatray Mane, Gouri Raj A, Reshma Reghu, Subhasmita Mohapatra, Sivapriya Marappan, Suraj T Gore, Subhendu Mukherjee, Girish Daginakatte, Kavitha Nellore, Shekar Chelur, Murali Ramachandra, Susanta Samajdar. Identification and characterization of paralogue selective CBP degraders for potential use in cancer therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6065.