2. Academic Validation
  3. Design, synthesis and in vitro biological evaluation of 2-aminopyridine derivatives as novel PI3Kδ inhibitors for hematological cancer

Design, synthesis and in vitro biological evaluation of 2-aminopyridine derivatives as novel PI3Kδ inhibitors for hematological cancer

  • Bioorg Med Chem Lett. 2023 Feb 15:82:129152. doi: 10.1016/j.bmcl.2023.129152.
Chengbin Yang 1,  Yimin Gong 2,  Yunjian Gao 2,  Mingli Deng 2,  Xiaofeng Liu 2,  Yongtai Yang 2,  Yun Ling 2,  Yu Jia 3,  Yaming Zhou 4
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai 200433, China; Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China.
  • 2 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai 200433, China.
  • 3 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai 200433, China. Electronic address: [email protected].
  • 4 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai 200433, China. Electronic address: [email protected].
PMID: 36706844 DOI: 10.1016/j.bmcl.2023.129152
Abstract

Phosphoinositide-3-kinase (PI3K) involves in regulation of proliferation, cell cycle, and Apoptosis, and is overexpressed in most of human malignant tumors. Therefore, the development of PI3K inhibitors has attracted great interest in tumor treatment. In this study, we designed and synthesized a series of 2-aminopyridine derivatives via a bioisosterism strategy. Among them, compound MR3278 showed superior PI3Kδ inhibitory activity (IC50 = 30 nM), as well as higher inhibitory activity to most of AML cells (e.g., MOLM-16 and Mv-4-11 cells with IC50 values of 2.6 μM and 3.7 μM, respectively) than Idelalisib. Further cell studies indicated that MR3278 could induce G2/M phase arrests and cell Apoptosis of Mv-4-11 cells via PI3K dependent pathway in a dose dependent manner. In addition, in silico physicochemical and ADMET evaluation revealed its drug-like properties with satisfactory toxicity profiles. These results indicate that MR3278 can be identified as a promising new lead compound to the current PI3Kδ Inhibitor and is worthy of further profiling.

Keywords

2-aminopyridine; Hematological malignancies; PI3Kδ inhibitor; Phosphatidylinositol 3-kinase.

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