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
- Eur J Med Chem. 2023 Sep 5;257:115514. doi: 10.1016/j.ejmech.2023.115514.
- 1. Department of Chemistry, Fudan University, Shanghai, 200438, China.
- 2. Department of Chemistry, Fudan University, Shanghai, 200438, China. Electronic address: [email protected].
- 3. SD Chem, Inc., San Diego, CA, 92128, USA.
- 4. ABA Chemicals Co., Ltd., Taicang, Jiangsu, 215400, China.
- 5. Department of Chemistry, Fudan University, Shanghai, 200438, China. Electronic address: [email protected].
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.