Orally Bioavailable CBP and p300 Selective Degraders for the Treatment of AR- and ER-dependent Cancers

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