Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads.
Mingzong LiZenon KonteatisNelamangala NagarajaYue ChenShubao ZhouGuangning MaStefan GrossKatya MarjonMarc L HyerEverton MandleyMax LeinAnil K PadyanaLei JinShuilong TongRachel PetersJoshua MurtieJeremy TravinsMatthew MedeirosPeng LiuVictoria FrankEvan T JuddScott A BillerKevin M MarksZhihua SuiSamuel K ReznikPublished in: Journal of medicinal chemistry (2022)
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).
Keyphrases
- resting state
- white matter
- functional connectivity
- end stage renal disease
- cerebral ischemia
- newly diagnosed
- ejection fraction
- chronic kidney disease
- emergency department
- blood brain barrier
- multiple sclerosis
- gene expression
- dna methylation
- copy number
- climate change
- highly efficient
- cerebrospinal fluid
- electronic health record
- drug discovery