Discovery of A2AR antagonist HTL1071/AZD4635 using SBDD
By Miles Congreve | Dec 13, 2019
About the Conference
“New Drugs in Development in Japan, Europe and the USA”
24th Japanese Foundation for Cancer Research-International Symposium on Cancer Chemotherapy (JFCR-ISCC)
11-12 December 2019
Miles Congreve, Chief Scientific Officer at Sosei Heptares, recently attended the 24th Japanese Foundation for Cancer Research-International Symposium on Cancer Chemotherapy (JFCR-ISCC) named “New Drugs in Development in Japan, Europe and the USA” held in Tokyo, Japan on 11-12 Dec and presented on discovery of A2AR antagonist AZD4635 (HTL1071) using SBDD. The presentation was based on the one given previously in the New Approaches in Medicinal Chemistry symposium in Cambridge, UK on 20 June 2019.
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 tumour 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 optimised 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-crystallisation. 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.