Identification of Novel Piperazinylquinoxaline Derivatives as Potent Phosphoinositide 3-Kinase (PI3K) Inhibitors

Peng Wu, Yi Su, Xianghong Guan, Xiaowen Liu, Jiankang Zhang, Xiaowu Dong, Wenhai Huang, Yongzhou Hu

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Background: Development of small-molecule inhibitors targeting phosphoinositide 3-kinase (PI3K) has been an appealing strategy for the treatment of various types of cancers.

Methodology/Principal Finding: Our approach was to perform structural modification and optimization based on previously identified morpholinoquinoxaline derivative WR1 and piperidinylquinoxaline derivative WR23 with a total of forty-five novel piperazinylquinoxaline derivatives synthesized. Most target compounds showed low micromolar to nanomolar antiproliferative potency against five human cancer cell lines using MTT method. Selected compounds showed potent PI3K alpha inhibitory activity in a competitive fluorescent polarization assay, such as compound 22 (IC50 40 nM) and 41 (IC50: 24 nM), which induced apoptosis in PC3 cells. Molecular docking analysis was performed to explore possible binding modes between target compounds and PI3K.

Conclusions/Significance: The identified novel piperazinylquinoxaline derivatives that showed potent PI3K alpha inhibitory activity and cellular antiproliferative potency may be promising agents for potential applications in cancer treatment.
Original languageEnglish
Article numbere43171
JournalP L o S One
Issue number8
Number of pages14
Publication statusPublished - 2012
Externally publishedYes

Bibliographical note

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


  • Apoptosis
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] A549 cell line cell_line human lung carcinoma cells HCT116 cell line cell_line human colon carcinoma cells PC3 cell line cell_line human prostate carcinoma cells HL60 cell line cell_line human promyelocytic leukemic cells KB cell line cell_line human mouth squamous cell carcinoma cells
  • Morpholinoquinoxaline derivative antineoplastic-drug, enzyme inhibitor-drug synthesis efficacy
  • Phosphoinositide 3-kinase 115926-52-8 EC
  • Piperazinylquinoxaline derivatives antineoplastic-drug, enzyme inhibitor-drug synthesis efficacy
  • 02508, Cytology - Human
  • 10802, Enzymes - General and comparative studies: coenzymes
  • 12512, Pathology - Therapy
  • 22002, Pharmacology - General
  • 22005, Pharmacology - Clinical pharmacology
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • 24008, Neoplasms - Therapeutic agents and therapy
  • Competitive fluorescent polarization assay laboratory techniques, bioassay techniques
  • Molecular docking laboratory techniques
  • MTT method laboratory techniques
  • Pharmacology
  • Tumor Biology


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