基于结构的羟基内酰胺优化，作为乳酸脱氢酶的强效细胞活性抑制剂。
Structure-based optimization of hydroxylactam as potent, cell-active inhibitors of lactate dehydrogenase.
作者信息
Wei BinQing, Robarge Kirk, Labadie Sharada S, Chen Jinhua, Corson Laura B, DiPasquale Antonio, Dragovich Peter S, Eigenbrot Charles, Evangelista Marie, Fauber Benjamin P, Hitz Anna, Hong Rebecca, Lai Kwong Wah, Liu Wenfeng, Ma Shuguang, Malek Shiva, O'Brien Thomas, Pang Jodie, Peterson David, Salphati Laurent, Sampath Deepak, Sideris Steven, Ultsch Mark, Xu Zijin, Yen Ivana, Yu Dong, Yue Qin, Zhou Aihe, Purkey Hans E
机构信息
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
出版信息
Bioorg Med Chem Lett. 2022 Mar 1;59:128576. doi: 10.1016/j.bmcl.2022.128576. Epub 2022 Jan 19.
Structure-based design was utilized to optimize 6,6-diaryl substituted dihydropyrone and hydroxylactam to obtain inhibitors of lactate dehydrogenase (LDH) with low nanomolar biochemical and single-digit micromolar cellular potencies. Surprisingly the replacement of a phenyl with a pyridyl moiety in the chemical structure revealed a new binding mode for the inhibitors with subtle conformational change of the LDHA active site. This led to the identification of a potent, cell-active hydroxylactam inhibitor exhibiting an in vivo pharmacokinetic profile suitable for mouse tumor xenograft study.
基于结构的设计被用于优化6,6-二芳基取代的二氢吡喃酮和羟基内酰胺，以获得具有低纳摩尔生化活性和个位数微摩尔细胞活性的乳酸脱氢酶（LDH）抑制剂。令人惊讶的是，在化学结构中用吡啶基部分取代苯基揭示了抑制剂的一种新结合模式，同时伴随LDHA活性位点的细微构象变化。这导致鉴定出一种强效的、具有细胞活性的羟基内酰胺抑制剂，其体内药代动力学特征适合小鼠肿瘤异种移植研究。
Zotero 插件