Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads.

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).

Use of a Smartphone App for Cochlear Implant Patients With Tinnitus.

Purpose Smartphone apps for tinnitus relief are now emerging; however, research supporting their use and effectiveness is lacking. Research has shown that Tinnitus Therapy sounds intended for individuals with acoustic hearing provide relief to some patients using cochlear implants (CIs) with tinnitus. Here, we evaluated the use and acceptability of a smartphone app to help CI patients with tinnitus. Method Participants completed a laboratory trial (n = 19) and an at-home trial (n = 14) using the ReSound Tinnitus Relief app to evaluate its acceptability and effectiveness in reducing their tinnitus. During the laboratory trial, participants selected a sound that was most acceptable in managing their tinnitus (termed chosen sound). Word recognition scores in quiet were obtained before and after sound therapy. Participants were randomly assigned to one of two groups for the at-home trial, that is, AB or BA, using (A) the chosen sound for 2 weeks and (B) the study sound (i.e., broadband noise at hearing threshold) for another 2 weeks. Ratings were collected weekly to determine acceptability and effectiveness of the app in reducing tinnitus loudness and annoyance. Results Results indicated that some, but not all, participants found their chosen sound to be acceptable and/or effective in reducing their tinnitus. A majority of the participants rated the chosen sound or the study sound to be acceptable in reducing their tinnitus. Word recognition scores for most participants were not adversely affected using the chosen sound; however, a significant decrease was observed for three participants. All 14 participants had a positive experience with the app during the at-home trial on tests of sound therapy acceptability, effectiveness, and word recognition. Conclusions Sound therapy using a smartphone app can be effective for many tinnitus patients using CIs. Audiologists should recommend a sound and a level for tinnitus masking that do not interfere with speech perception.

MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage.

The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.

The in vivo performance of a novel thermal accelerant agent used for augmentation of microwave energy delivery within biologic tissues during image-guided thermal ablation: a porcine study.

OBJECTIVES: To investigate the effects of a novel caesium-based thermal accelerant (TA) agent on ablation zone volumes following in vivo microwave ablation of porcine liver and skeletal muscle, and to correlate the effects of TA with target organ perfusion. MATERIALS AND METHODS: This prospective study was performed following institutional animal care and use committee approval. Microwave ablation was performed in liver and resting skeletal muscle in eight Sus scrofa domesticus swine following administration of TA at concentrations of 0 mg/mL (control), 100 mg/mL and 250 mg/mL. Treated tissues were explanted and stained with triphenyltetrazolium chloride (TTC) for quantification of ablation zone volumes, which were compared between TA and control conditions. Hematoxylin and eosin (H&E) staining was also performed for histologic analysis. General mixed modelling with a log-normal distribution was used for all quantitative comparisons (p = 0.05). RESULTS: A total of 28 ablations were performed in the liver and 18 in the skeletal muscle. The use of TA significantly increased ablation zone volumes in a dose-dependent manner in both the porcine muscle and liver (p < 0.01). Both the absolute mean ablation zone volume and percentage increase in ablation zone volume were greater in the resting skeletal muscle than in the liver. In one swine, a qualitative mitigation of heat sink effects was observed by TTC and H&E staining. Non-lethal polymorphic ventricular tachycardia was identified in one swine, treated with intravenous amiodarone. CONCLUSIONS: 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.

Evaluation of a Novel Thermal Accelerant for Augmentation of Microwave Energy during Image-guided Tumor Ablation.

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.

Liver lesions in demersal fishes near a large ocean outfall on the San Pedro Shelf, California.

The prevalence of toxicopathic liver lesions in demersal fish on the San Pedro Shelf, California was determined for a 15-year period (1988-2003). Fish livers were sampled at fixed locations as part of the Orange County Sanitation Districts (OCSD) ocean monitoring program. Histopathological examination of selected fish liver tissues was studied to determine whether the wastewater discharge had affected fish health. The prevalence of toxicopathic lesion classes neoplasms (NEO), preneoplastic foci of cellular alteration (FCA), and hydropic vacuolation (HYDVAC) varied among species and locations. For all species sampled, severe lesions occurred in 6.2% of the fish examined (n=7,694). HYDVAC (4.1%) was the most common toxicopathic lesion type followed by FCA (1.4%) and NEO (0.7%). HYDVAC occurred only in white croaker (Genyonemus lineatus), accounting for 84.8% of the toxicopathic lesions for this species. Prevalence of HYDVAC, NEO, and FCA in white croaker was 15.2, 2.0, and 0.7%, respectively. The prevalence of HYDVAC and NEO in white croaker increased with age and size but there was no sexual difference. A linear regression model was used for hypothesis testing to account for significant differences in fish size (and age for croakers) at the different sampling locations. This analysis showed that for HYDVAC there was no spatial or location effect for lesion rate or size/age of onset. For NEO, the model predicted that white croaker near the wastewater outfall may acquire these lesions at a smaller size/younger age, and at a higher rate, than at other sites. However, this result may be biased due to the unequal size frequency distributions and the low prevalence of NEO in white croaker at the different sampling sites. Bigmouth sole (Hippoglossina stomata) had a prevalence of FCA and NEO of 1.3 and 0.35%, respectively, but the prevalence and distribution of lesions was too few for statistical testing. There was no sexual difference for lesion prevalence in hornyhead turbot (Pleuronichthys verticalis) and the prevalence of FCA and NEO was 3.4 and 0.37%, respectively. FCA prevalence increased with size in hornyhead turbot and there were no significant spatial differences for lesion rates and fish size at lesion onset. Overall, consistent spatial differences for lesion prevalence were not demonstrated and highlight the analytical difficulties of detecting a possible point source impact when the effect is rare, correlated with the size/age structure of the population, and may be caused by exposure to unknown multiple sources. Thus, the usefulness of liver histopathology as a point-source monitoring tool is best applied to where the spatial scale of impact generally exceeds the home range of the target species.