Next Generation Thiazolyl Ketone Inhibitors of Cytosolic Phospholipase A2 a: from Synthesis to Chemotherapeutic Mechanism of Action
Eicosanoids participate in the pathologies of inflammation and carcinogenesis and limiting their production by inhibiting group IVA cytosolic phospholipase A2 (cPLA2a) is a potential approach to cancer treatment. Here we report the synthesis of a new generation of thiazolyl ketone inhibitors of cPLA2a starting from compound GK470 (AVX235), and the discovery of a more potent and selective lead, GK420 (AVX420), with significant chemotherapeutic properties. A cancer cell line screen revealed the selective growth inhibitory effects of AVX420 in acute leukemias, uncovering a novel function of cPLA2a to promote cancer cell survival during oxidative stress by epigenetic control of tumour suppressor gene transcription. Moreover, we showed that in sensitive cells, AVX420 increased intracellular reactive oxygen species (ROS) and instigated a transcriptional response resulting in cell death.  Our study suggests AVX420 has the potential to treat acute leukemias, and other cancers with specific adaptations to a high ROS burden. Overall design: To investigate the effect of cPLA2alpha inhibition on cell survival signaling in CCRF-CEM cells, we treated cells with either vehicle (VEH CTRL) or the cPLA2alpha inhibitor AVX420 (AVX420) for 1 hour and 6 hours and extracted total RNA and ribsome-associated RNA, or for 16 hours and extracted just total RNA. As a positive control for translational repression, cells were treated with the mTOR inhibior Torin-1 for 1 hour and both the total and ribosome-associated RNA were extracted. Experiments were performed in duplicates (Biorep 1 and Biorep 2)