Astex Pharmaceuticals is presenting key data on its novel small molecule therapeutics at the 36th EORTC-NCI-AACR Symposium on molecular targets and cancer therapeutics in Barcelona, Spain, from October 23-25, 2024. The presentations highlight advances in both preclinical and clinical development of ASTX528 and ASTX295.
ASTX528: A Novel CBP/p300 HAT Domain Inhibitor
ASTX528, discovered using Astex's fragment-based drug discovery approach, is a novel small molecule inhibitor targeting the HAT domain of CBP/p300. CBP (CREB-binding protein) and p300 are lysine acetyltransferases and transcriptional cofactors implicated in various human cancers. Previous attempts to inhibit CBP/p300 using bromodomain (BRD) inhibitors have encountered dose-limiting tolerability issues. Astex hypothesized that targeting the HAT domain directly might offer an improved therapeutic window. Preclinical data presented at the symposium demonstrates potent in vivo activity and a favorable safety profile for ASTX528 in preclinical species. The presentations will describe the effects of CBP/p300 HAT domain inhibition in preclinical models of AR- and ER-driven cancers and the characterisation of ASTX528, a potent, fragment-derived CBP/p300 HAT domain inhibitor with a low predicted human dose and promising preliminary toxicity evaluation.
ASTX295: Bone Marrow-Sparing MDM2 Antagonist
ASTX295 is an orally available, potent inhibitor of the p53-MDM2 protein-protein interaction. It was designed to overcome the on-target toxicities, specifically dose-limiting haematological toxicities, observed with first-generation MDM2 antagonists. ASTX295 exhibits a clean CYP/hERG profile and a shorter human half-life, allowing for pulsatile pathway modulation while avoiding myelosuppression. This bone marrow-sparing characteristic potentially permits a differentiated safety profile. Data presented at the symposium includes identification of biomarkers predictive of response to ASTX295 in solid tumors carrying wild-type p53, potentially enabling better patient selection for future clinical trials. Further research demonstrates that pulsatile induction of the p53 pathway by ASTX295 enhances its therapeutic index in vivo, suggesting optimized dosing strategies. ASTX295 was discovered by Astex in collaboration with the Cancer Research UK Drug Discovery Unit at Newcastle University. Astex has an exclusive license to research, develop and commercialise ASTX295 under its drug discovery alliance agreement with Newcastle University and Cancer Research Technology Limited.
Maria Ahn from Astex Pharmaceuticals presented an oral presentation on "From a Preclinical Therapeutic Concept to the Clinic. ASTX295: Discovery of a bone marrow sparing MDM2 antagonist".
Astex is actively seeking potential partners for the further development of ASTX528.
