1. Academic Validation
  2. 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

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.
Ruiqing Xiang 1 Mingzhu Lu 1 Tianze Wu 1 Chengbin Yang 1 Yu Jia 1 Xiaofeng Liu 1 Mingli Deng 2 Yu Ge 3 Jun Xu 4 Tong Cai 4 Yun Ling 1 Yaming Zhou 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Fudan University, Shanghai, 200438, China.
  • 2 Department of Chemistry, Fudan University, Shanghai, 200438, China. Electronic address: mldeng@fudan.edu.cn.
  • 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: ymzhou@fudan.edu.cn.
Abstract

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.

Keywords

Acute myeloid leukemia; N-pyridinyl amide scaffold; PIM inhibitors; Structure-activity relationship.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155529
    PIM抑制剂
    Pim