No abstract

Inhibition of the S-adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998, and a potent, but limited brain-penetrant compound, AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).

The primary challenge in thermal ablation of liver tumors (e.g. hepatocellular carcinoma and hepatic colorectal cancer) is the relatively high recurrence rate (~30%) for which incomplete ablation at the periphery of the tumor is the most common reason. In an attempt to overcome this, we have developed a novel thermal accelerant (TA) agent capable of augmenting microwave energy from a distance normally unattainable by a single microwave ablation antenna. This cesium-based block co-polymer compound transforms from a liquid to a gel at body temperature and is intrinsically visible by computed tomography. Using an agarose phantom model, herein we demonstrate that both the rate and magnitude of temperature increase during microwave ablation were significantly greater in the presence of TA when compared with controls. These results suggest robust augmentation of microwave energy, and may translate into larger ablation zone volumes within biologic tissues. Further work using in vivo techniques is necessary to confirm these findings.

The use of a novel TA agent significantly increased mean ablation zone volumes following microwave ablation using a porcine model. The relationship between TA administration and ablation size was dose-dependent and inversely proportional to the degree of target organ perfusion, and a qualitative reduction in heat-sink effects was observed.