Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt’s lymphoma anti-tumor activity

Abstract

// Nicola J. Curtis 1 , Lorraine Mooney 1 , Lorna Hopcroft 2 , Filippos Michopoulos 1 , Nichola Whalley 2 , Haihong Zhong 3 , Clare Murray 4,6 , Armelle Logie 1 , Mitchell Revill 1 , Kate F. Byth 5 , Amanda D. Benjamin 4 , Mike A. Firth 1 , Stephen Green 1 , Paul D. Smith 2 and Susan E. Critchlow 2 1 iMED Oncology, AstraZeneca, Alderley Park, Cheshire, UK 2 iMED Oncology, AstraZeneca, Cambridge, UK 3 MedImmune, One MedImmune Way, Gaithersburg, MD, USA 4 iMED DSM, AstraZeneca, Cambridge, UK 5 iMED Oncology, AstraZeneca, Gatehouse Park, Waltham, Massachusetts, MA, USA 6 C4X Discovery, Manchester, UK Correspondence to: Susan E. Critchlow, email: // Keywords : AZD3965, MCT1, metabolism, lactate Received : November 16, 2016 Accepted : May 15, 2017 Published : May 25, 2017 Abstract Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab. AZD3965 is a potent inhibitor of MCT1 with activity against MCT2 but selectivity over MCT3 and MCT4. In vitro , AZD3965 inhibited the growth of a range of cell lines especially haematological cells. Inhibition of MCT1 by AZD3965 inhibited lactate efflux and resulted in accumulation of glycolytic intermediates. In vivo , AZD3965 caused lactate accumulation in the Raji Burkitt’s lymphoma model and significant tumor growth inhibition. Moreover, AZD3965 can be combined with doxorubicin or rituximab, components of the R-CHOP standard-of-care in DLBCL and Burkitt’s lymphoma. Finally, combining lactate transport inhibition by AZD3965 with GLS1 inhibition in vitro , enhanced cell growth inhibition and cell death compared to monotherapy treatment. The ability to combine AZD3965 with novel, and standard-of-care inhibitors offers novel combination opportunities in haematological cancers.