Orally Bioavailable CBP and p300 Selective Degraders for the Treatment of AR- and ER-dependent Cancers
European Journal of Cancer(2022)
Abstract
E1A binding protein (p300) and its paralog CREB binding protein (CBP or CREBBP) are ubiquitously expressed histone acetyl transferases (HAT) that act by scaffolding or as co-activator and enhancer of different transcription factors like HIF1a, BRCA-1, p53, c-Myc, Estrogen receptor (ER) and Androgen receptor (AR). CBP and p300 are multidomain proteins that harbour different functional units imperative for chromatin remodelling and transcription like Bromodomain (BD), Histone acetyl transferase (HAT) domain, KIX domain etc. These two closely related epigenetic modulators are known to play oncogenic role in variety of cancers. In breast and prostate cancers, in addition to serving as transcriptional coactivators, CBP/p300 also acetylates AR and ER and regulates their function by enhancing stability. Therefore, unlike inhibitors a degrader of CBP and p300 is expected to show a stronger impact on the stability and transcriptional activity of both AR and ER (including mutant forms) leading to pronounced therapeutic responses by eliminating both the transcriptional co-activator and acetylation functions. Additionally, it might be possible with degraders to obtain paralog selectivity (p300 vs CBP) to achieve required pharmacological activity but with better tolerability. In an effort to identify novel degraders of CBP and p300 for potential treatment of breast and prostate cancers, a variety of hetero bi-functional molecules were synthesized by conjugating selective CBP/p300 bromodomain binders with various E3-ligase specific ligands. Rational design approach guided by our proprietary ternary complex modeling algorithm, ALMOND (ALgorithm for MOdeling Neo substrate Degraders) resulted in the identification of structurally unique highly selective CBP/p300 degraders, which were further optimized for potency, selectivity and ADME properties. The lead orally bioavailable CBP/p300 degrader compounds showed more pronounced cellular effects and apoptosis in multiple cancer cell lines including AR-dependent prostate and ER-dependent breast cancer cells as a single agent due to complete degradation of the targets and sustained downregulation of signaling network downstream of CBP and p300. In comparison with inhibitors, there was a remarkable and durable inhibition of the levels of AR and ER as well as their target genes observed with degraders. In vivo studies, including efficacy and safety assessments are planned to further understand the therapeutic potential and safety margin for these degraders. Efforts to improve paralogue selectivity by modifying key interactions of CBP/p300 are also in progress. No conflict of interest.
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Key words
p300 selective degraders,bioavailable cbp,er-dependent
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