Discovery and characterisation of quinazolines and 8-Azaquinazolines as NLRP3 agonists with oral bioavailability in mice.

The NLRP3 inflammasome is a multiprotein complex that plays a critical role in activating the immune system in response to danger signals. Small molecule agonists of NLRP3 may offer clinical benefits in cancer immunology either as a monotherapy or in combination with checkpoint blockade, where it is hypothesised that their application can help to initiate an antitumor immune response. In this study, we report the discovery of quinazolines and 8-azaquinazolines as NLRP3 agonists and their chemical optimization to afford compounds with oral bioavailability in mice. We confirm that these compounds engage the NLRP3 inflammasome by verifying their dependence upon lipopolysaccharide (LPS) priming for cytokine release and the activation of Caspase-1. We further demonstrate pathway engagement through loss of activity in an NLRP3-knockout THP1 cell line. Based on their pharmacokinetic profile and biological activity, these compounds represent valuable tools to evaluate the therapeutic potential of NLRP3 activation in a pre-clinical setting.

Targeting PRC2 for the treatment of cancer: an updated patent review (2016 - 2020).

INTRODUCTION: PRC2 is a histone methyltransferase complex associated with several cancer types. Tazemetostat was recently approved as the first inhibitor targeting the catalytic subunit EZH2 and several other EZH2 inhibitors are now under clinical evaluation. Beyond EZH2, researchers have also explored other approaches including PRC2 activators, dual agents inhibiting both EZH1 and EZH2, allosteric inhibitors binding to EED, and compounds which induce the degradation of PRC2 constituent proteins. AREAS COVERED: This review provides an overview of anticancer therapies targeting PRC2 during the period 2016-2020 including clinical trials, patents and the scientific literature. EXPERT OPINION: The approval of tazemetostat marks the clinical validation of EZH2 for the treatment of cancer. Despite this success many questions remain; for instance, tazemetostat was briefly placed on clinical hold for safety concerns, while another EZH2 inhibitor (GSK126) demonstrated insufficient efficacy during a Phase I/II trial. It is important to understand these risks as PRC2 therapies progress through clinic evaluation. Alternative approaches to target PRC2 may offer distinct advantages over the inhibition of EZH2, including the potential to overcome EZH2 resistance mutations. However, these emerging modalities may also incur new challenges as they progress toward the clinic. Nonetheless, the diversity of agents under development represents a wealth of therapeutic options for future patients.