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Acta Pharmacol Sin. 2018 Nov;39(11):1816-1822. doi: 10.1038/s41401-018-0057-z. Epub 2018 Jul 10.

High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds.

Author information

1
The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, China.
2
Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand.
3
The Maurice Wilkins Centre, Auckland, New Zealand.
4
Auckland Cancer Society Research Centre, Auckland, New Zealand.
5
School of Biological Sciences, The University of Auckland, Auckland, New Zealand.
6
The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, China. mwwang@simm.ac.cn.
7
School of Pharmacy, Fudan University, Shanghai, 201203, China. mwwang@simm.ac.cn.

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors.

KEYWORDS:

PI3 kinase; PI3Kα H1047R; high throughput screening; inhibitors; molecular modeling.

PMID:
29991713
PMCID:
PMC6289374
[Available on 2019-11-01]
DOI:
10.1038/s41401-018-0057-z
[Indexed for MEDLINE]

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