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

Chengbin Yang; Chenyue Xu; Zhipeng Li; Yi Chen; Tianze Wu; Hui Hong; Mingzhu Lu; Yu Jia; Yongtai Yang; Xiaofeng Liu; Mingli Deng; Zhenxia Chen; Qingquan Li; Yun Ling; Yaming Zhou

doi:10.1016/j.ejmech.2021.113661

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. Epub 2021 Jun 21.

Authors

Chengbin Yang¹, Chenyue Xu², Zhipeng Li¹, Yi Chen¹, Tianze Wu¹, Hui Hong³, Mingzhu Lu¹, Yu Jia¹, Yongtai Yang¹, Xiaofeng Liu¹, Mingli Deng¹, Zhenxia Chen¹, Qingquan Li⁴, Yun Ling⁵, Yaming Zhou⁶

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: 061101040@fudan.edu.cn.
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: yunling@fudan.edu.cn.
⁶ Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China. Electronic address: ymzhou@fudan.edu.cn.

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.

MeSH terms

Animals
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
Class I Phosphatidylinositol 3-Kinases / metabolism
Drug Design*
G1 Phase Cell Cycle Checkpoints / drug effects
Half-Life
Humans
Indoles / chemistry*
Indoles / metabolism
Indoles / pharmacology
Indoles / therapeutic use
Leukemia, Myeloid, Acute / drug therapy
Leukemia, Myeloid, Acute / pathology
Mice
Mice, Nude
Molecular Docking Simulation
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis*
Phosphoinositide-3 Kinase Inhibitors / metabolism
Phosphoinositide-3 Kinase Inhibitors / pharmacology
Phosphoinositide-3 Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Transplantation, Heterologous

Substances

Indoles
Phosphoinositide-3 Kinase Inhibitors
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human
Proto-Oncogene Proteins c-akt