Zhang Xiansheng, Zhu Xinyuan, Li Yong, Li Yan, Luo Wen, Khan Maaz, Pan Jiamin, Pan Hong, Xie Hua, Zhao Guilong
College of Food Science and Pharmaceutical Engineering, Zaozhuang University, Zaozhuang, 277160, China.
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
Curr Med Chem. 2025 Jan 8. doi: 10.2174/0109298673320136241024054435.
Branched-chain amino acids (BCAAs) are essential amino acids for humans and play an indispensable role in many physiological and pathological processes. Branched-chain amino acid aminotransferase (BCAT) is a key enzyme that catalyzes the metabolism of BCAAs. BCAT is upregulated in many cancers and implicated in the development and progress of some other diseases, such as metabolic and neurological diseases; and therefore, targeting BCAT might be a potential therapeutic approach for these diseases. There are two isoforms of BCAT, i.e., cytoplasmic BCAT1 (or BCATc) and mitochondrial BCAT2 (or BCATm). The discovery of BCAT inhibitors was initiated by Warner-Lambert, a subsidiary of Pfizer, in 2000, followed by many other pharmaceutical companies, such as GlaxoSmithKline (GSK), Ergon, Icagen, Agios, and Bayer. Strategies of high-throughput screening (HTS), DNA-Encoded library technology (ELT), and fragment-based screening (FBS) have been employed for hit identification, followed by structural optimization. Despite low selectivity, both BCAT1 and BCAT2 selective inhibitors were individually developed, each with a few chemical structural classes. The most advanced BCAT1 inhibitor is BAY-069, discovered by Bayer, which has a potent enzymatic inhibitory activity against BCAT1 and a decent in vitro and in vivo pharmacokinetic profile but displayed weaker cellular inhibitory activity and almost no anti-proliferative activity. There are no BCAT inhibitors currently under investigation in clinical trials. Further studies are still needed to discover BCAT inhibitors with a more druggable profile for proof of concept. This review focuses on the latest progress of studies on the understanding of the physiology and pathology of BCAT and the discovery and development of BCAT inhibitors. The structure-activity relationship (SAR) and the druggability, and the challenges of BCAT inhibitors are discussed, with the aim of inspiring the discovery and development of BCAT inhibitors in the future.
支链氨基酸（BCAAs）是人体必需氨基酸，在许多生理和病理过程中发挥着不可或缺的作用。支链氨基酸转氨酶（BCAT）是催化BCAAs代谢的关键酶。BCAT在许多癌症中上调，并与其他一些疾病（如代谢性疾病和神经疾病）的发生和发展有关；因此，靶向BCAT可能是治疗这些疾病的一种潜在方法。BCAT有两种同工型，即细胞质BCAT1（或BCATc）和线粒体BCAT2（或BCATm）。2000年，辉瑞公司的子公司华纳-兰伯特公司率先开展了BCAT抑制剂的研究，随后其他许多制药公司，如葛兰素史克（GSK）、厄尔贡、伊卡根、阿吉奥斯和拜耳等也纷纷跟进。高通量筛选（HTS）、DNA编码文库技术（ELT）和基于片段的筛选（FBS）等策略已被用于发现活性分子，随后进行结构优化。尽管选择性较低，但BCAT1和BCAT2选择性抑制剂都已分别开发出来，各自有几个化学结构类别。最先进的BCAT1抑制剂是拜耳公司发现的BAY-069，它对BCAT1具有强大的酶抑制活性，体外和体内药代动力学特性良好，但细胞抑制活性较弱，几乎没有抗增殖活性。目前尚无BCAT抑制剂正在进行临床试验。仍需要进一步研究以发现具有更适合成药特性的BCAT抑制剂，以进行概念验证。本综述重点介绍了对BCAT生理和病理的认识以及BCAT抑制剂的发现与开发的最新研究进展。讨论了构效关系（SAR）和成药性以及BCAT抑制剂面临的挑战，旨在激发未来BCAT抑制剂的发现与开发。
