Discovery of a high potent PIM kinase inhibitor for acute myeloid leukemia based on N-pyridinyl amide scaffold by optimizing the fragments toward to Lys67 and Asp128/Glu171

• Published in: European journal of medicinal chemistry 2023-09, Vol.257, p.115514-115514, Article 115514
• Main Authors: Xiang, Ruiqing, Lu, Mingzhu, Wu, Tianze, Yang, Chengbin, Jia, Yu, Liu, Xiaofeng, Deng, Mingli, Ge, Yu, Xu, Jun, Cai, Tong, Ling, Yun, Zhou, Yaming
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; N-pyridinyl amide scaffold; PIM inhibitors; Structure-activity relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115514

Despite the recent development of PIM inhibitors based on N-(pyridin-3-yl)acetamide scaffold for acute myeloid leukemia (AML), the structural-activity relationship (SAR) associated with the effects of positional isomerization of N toward to Lys67 and freedom of solvent fragment toward to Asp128/Glu171 still remains an open question. In this work, a structurally novel compound based on N-pyridinyl amide was designed by fragment hybridization and then our SAR exploration revealed that the positional isomerization would lead to a decrease in activity, while increase of the freedom of solvent fragment by breaking the intramolecular hydrogen bond unprecedentedly leads to an increase in activity. These studies finally resulted in the screening out of a potent PIM inhibitor FD1024 (compound 24) which exerts strong antiproliferative activity against the tested AML cell lines and achieves profound antitumor efficacy in mice at well-tolerated dose schedules. The structural-activity relationship (SAR) studies focused on optimizing the fragments toward to Lys67 and Asp128/Glu171 based on N-pyridinyl amide scaffold have led to the screening out of a high potent PIM kinase inhibitor (compound FD1024) for acute myeloid leukemia. [Display omitted] •Comprehensive studies on N-pyridinyl amide scaffold for PIM inhibitors' structure-activity relationship were conducted.•Our SAR study led to the identification of FD1024 as a highly potent PIM inhibitor.•Our in-vitro and in-vivo evaluations validate the anti-tumor efficacy of FD1024.