Discovery of A2AR Antagonist AZD4635 (HTL1071) using Structure-based Drug Discovery (SBDD)
By Miles Congreve | Jun 21, 2019
New Approaches in Medicinal Chemistry
20 June 2019
Brabaham Research Campus, Cambridge, UK
Society of Chemistry Industry
Adenosine A2A Receptor (A2AR) antagonists are an emerging class of agents for the treatment of cancers alone, and in combination with other therapeutic agents. Several studies support accumulation of extracellular adenosine in the tumor microenvironment as a critical mechanism in immune evasion implicating A2AR antagonists for use in immune-oncology. The A2AR antagonist mechanism is currently being validated in the clinic by a number of the key oncology players.
Sosei Heptares has a core platform called the StaR® technology that facilitates generation of optimized membrane protein samples for use in biophysical and structure-determination techniques. We have been pursuing structure-based drug discovery (SBDD) approaches for the discovery of A2AR antagonists for a number of years. Within this body of work we have identified a number of chemical series binding to the orthosteric site of receptor, illuminated by ligand-receptor X-ray co-crystallization. The identification of a clinical candidate AZD4635 (HTL1071) will be described, along with biological data supporting its use in oncology generated by our partner AstraZeneca.