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

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).

Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability

“…Initial SAR efforts started from modulating the R 2 group that is conjugated to the tricyclic fragment because the docking results suggested that there existed a cavity near the position of the methyl group of 8 (Figure 3A). As expected, the substitution of methyl to longer chains, such as isopropyl (12), methylcyanide (13), methoxyethane (14), and 3-methyloxetane (15), led to several active compounds that were similar to 8 in MAT2A and proliferation inhibition (Table 2). Interestingly, the substitution of an amide in R 2 (16) resulted in a >2-fold loss in potency when compared with compound 8.…”

“…The halogen–carbonyl interactions have been proved to improve the binding free enthalpy between proteins and ligands . The halogen–carbonyl interactions between AGI-43192 and the above two residues were previously observed in the cocrystal structure Figure C).…”

Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors

“…It has been found that after long-term high-dose administration of AGI-24512 , MAT2A has an A276 V point mutation, which obstructs the binding of the inhibitor to the protein, resulting in drug resistance to allosteric inhibitors . In addition, in in vivo efficacy experiments in mice, there were cases of weight loss in mice caused by inhibitor intolerance, indicating the possibility of unknown off-target effects. , Thus, the discovery of novel chemotypes serving as MAT2A inhibitors is urgently needed. For example, dimer inhibitor strategies can be used to develop inhibitors that target MAT2A dimers or to develop inhibitors with new binding modes using possible strategies within the medicinal chemistry range, such as stent hopping, high-throughput screening, and fragment screening.…”

“…Another publication from Agios described a series of novel MAT2A inhibitors (Figure ). , This series of compounds was developed to penetrate the blood–brain barrier (BBB) and modulate SAM levels in the brain, which will create new opportunities for improving the potential therapeutic effects of SAM modulation in the central nervous system. AGI-41998 ( 12 ) exhibits good activity and brain penetration.…”

“…Many studies have disclosed cocrystalline complexes of MAT2A with allosteric inhibitors, providing crucial information on binding modes. ,,, Pfizer researchers resolved the structure of the MAT2A–- 6 complex to 2.06 Å resolution (PDB code 5UGH). The crystal structure shows that 6 binds to the MAT2A dimer interface, which overlaps with the regulatory protein–protein interaction site of MAT2B, approximately 25 Å from the substrate binding site (Figure A) .…”