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

Authors: Jia Wang1, Grace Qun Gong1,2,3, Yan Zhou1, Woo-Jeong Lee2, Christina Maree Buchanan2,3, William Alexander Denny3,4, Gordon William Rewcastle3,4, Jackie Diane Kendall4, James Michael Jeremy Dickson3,5, Jack Urquhart Flanagan3,4, Peter Robin Shepherd2,3, De-Hua Yang1, Ming-Wei Wang1,6
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 School of Pharmacy, Fudan University, Shanghai 201203, China
Correspondence to: Ming-Wei Wang:,
DOI: 10.1038/s41401-018-0057-z
Received: 29 March 2018
Accepted: 30 May 2018
Advance online: 10 July 2018


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

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