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

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Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-03-16 , DOI: 10.1021/acs.jmedchem.1c01595
Mingzong Li ₁ , Zenon Konteatis ₁ , Nelamangala Nagaraja ₁ , Yue Chen ₁ , Shubao Zhou ₂ , Guangning Ma ₂ , Stefan Gross ₁ , Katya Marjon ₁ , Marc L Hyer ₁ , Everton Mandley ₁ , Max Lein ₁ , Anil K Padyana ₁ , Lei Jin ₁ , Shuilong Tong ₃ , Rachel Peters ₁ , Joshua Murtie ₁ , Jeremy Travins ₁ , Matthew Medeiros ₁ , Peng Liu ₁ , Victoria Frank ₁ , Evan T Judd ₁ , Scott A Biller ₁ , Kevin M Marks ₁ , Zhihua Sui ₁ , Samuel K Reznik ₁

Affiliation

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).

中文翻译：

利用基于结构的药物设计来识别下一代 MAT2A 抑制剂，包括脑渗透和外周有效的线索

抑制产生S-腺苷甲硫氨酸 (SAM) 的代谢酶甲硫氨酸腺苷转移酶 2A (MAT2A) 在药物化学领域引起了极大的兴趣，因为它可以作为癌症中的合成致死靶标，同时缺失甲基硫腺苷磷酸化酶(MTAP) 基因。在这里，我们报告了具有不同体内特性的新型 MAT2A 抑制剂的鉴定，这可能会增强它们在治疗患者中的效用。经过高通量筛选后，我们成功应用了一流的 MAT2A 抑制剂AG-270中基于结构的设计经验，快速重新设计和优化了我们最初的两种新先导化合物：脑渗透化合物，AGI-41998和一种有效但有限的脑渗透化合物AGI-43192。我们希望脑渗透性 MAT2A 抑制剂的鉴定和首次公开将为探索 SAM 调节在中枢神经系统 (CNS) 中的潜在治疗效果创造新的机会。

更新日期：2022-03-16

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