2. Academic Validation
  3. Bioisosteric replacements of the indole moiety for the development of a potent and selective PI3Kδ inhibitor: Design, synthesis and biological evaluation

Bioisosteric replacements of the indole moiety for the development of a potent and selective PI3Kδ inhibitor: Design, synthesis and biological evaluation

  • Eur J Med Chem. 2021 Nov 5;223:113661. doi: 10.1016/j.ejmech.2021.113661.
Chengbin Yang 1,  Chenyue Xu 2,  Zhipeng Li 1,  Yi Chen 1,  Tianze Wu 1,  Hui Hong 3,  Mingzhu Lu 1,  Yu Jia 1,  Yongtai Yang 1,  Xiaofeng Liu 1,  Mingli Deng 1,  Zhenxia Chen 1,  Qingquan Li 4,  Yun Ling 5,  Yaming Zhou 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
  • 2 Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • 3 Lyrae Therapeutics, L.L.C., Shanghai, 200438, China.
  • 4 Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
  • 5 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China; Zhuhai-Fudan Innovation Institute, Zhuhai, Guangdong, 519000, China. Electronic address: [email protected].
  • 6 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 34237636 DOI: 10.1016/j.ejmech.2021.113661
Abstract

Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). In vitro studies revealed that FD223 displays high potency (IC50 = 1 nM) and selectivity (29-51 fold over other PI3K isoforms) against PI3Kδ, and exhibits efficient inhibition of the proliferation of AML cell lines (MOLM-16, HL-60, EOL-1 and KG-1) by suppressing p-AKT Ser473 thus causing G1 phase arrest during the cell cycle. Further given the favorable pharmacokinetic (PK) profiles of FD223, in vivo studies were evaluated using xenograft model in nude mice, confirming its significant antitumor efficacy meanwhile with no observable toxicity. All these results are comparable to the positive group of Idelalisib (CAL-101), indicating that FD223 has potential for further development as a promising PI3Kδ Inhibitor for the treatment of leukemia such as AML.

Keywords

Bioisosteric replacement; Indole; Phosphatidylinotitol 3-kinase; Selective-PI3Kδ inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-132231
    98.68%, PI3Kδ Inhibitor