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

Nicola J. Curtis, Lorraine Mooney, Lorna Hopcroft, Filippos Michopoulos, Nichola Whalley, Haihong Zhong, Clare Murray, Armelle Logie, Mitchell Revill, Kate F. Byth, Amanda D. Benjamin, Mike A. Firth, Stephen Green, Paul D. Smith and Susan E. Critchlow _

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Oncotarget. 2017; 8:69219-69236. https://doi.org/10.18632/oncotarget.18215

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Abstract

Nicola J. Curtis1, Lorraine Mooney1, Lorna Hopcroft2, Filippos Michopoulos1, Nichola Whalley2, Haihong Zhong3, Clare Murray4,6, Armelle Logie1, Mitchell Revill1, Kate F. Byth5, Amanda D. Benjamin4, Mike A. Firth1, Stephen Green1, Paul D. Smith2 and Susan E. Critchlow2

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.


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