LAUSR

Cyclin-dependent kinase 9 (Cdk9) is a serine/threonine kinase that regulates elongation of transcription through phosphorylation of RNA polymerase II at serine 2 (pSer2-RNAPII). Transient inhibition of Cdk9 results in modulation of genes with short-lived transcripts and labile proteins, thereby representing a potential therapeutic opportunity in tumors dependent upon oncogenes fitting these criteria. Mcl1, an anti-apoptotic protein that has been linked to increased survival and chemotherapy resistance in various cancers, and Myc, a proto-oncogenic transcription factor that coordinates diverse transcription programs and is over-expressed, amplified, or translocated in many cancers, are two such oncogenes. AZ’5576 is a potent, highly selective, and orally bioavailable inhibitor of Cdk9 that inhibits Cdk9 enzyme activity with an IC50 In vitro screening assays reveal about half (19/35) of NHL cell lines undergo cell death in response to AZ’5576, demonstrating a potency 55% after 6 hour treatment. Combining AZ’5576 with a BTK inhibitor further enhances cell death compared to that observed with either single agent alone in BTK inhibitor-sensitive ABC-DLBCL cell lines. Consistent with the in vitro data, significant anti-tumor activity was associated with short-term reduction of pSer2-RNAPII tumor levels after intermittent dosing of AZ’5576 in a mouse xenograft model of ABC-DLBCL cell line OCILY10. Similarly, combining AZ’5576 with a BTK inhibitor in vivo drove tumors into regression (combination=199% TGI) compared to the partial TGI from either single agent alone (AZ’5576=79% TGI, Acalabrutinib=58% TGI) in the OCILY10 xenograft model. Finally, in an agressive Eµ-Myc transgenic mouse model of B-cell lymphoma, AZ’5576 treatment results in potent induction of apoptosis in vitro and a greater than 50 day increase in median overall survival in vivo. Together, these results highlight the therapeutic potential for selective CDK9 inhibition in the treatment of patients with non-Hodgkin lymphoma. Citation Format: Justin Cidado, Theresa Proia, Gareth Gregory, Izabela Todorovski, Scott Boiko, Maryann San Martin, Ricky Johnstone, Lisa Drew. AZ’5576, a selective CDK9 inhibitor, demonstrates in vitro and in vivo activity in diverse preclinical models of non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4295. doi:10.1158/1538-7445.AM2017-4295