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Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3Kα H1047R mutant inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2018 Oct 05; Vol. 158, pp. 707-719. Date of Electronic Publication: 2018 Sep 06. - Publication Year :
- 2018
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Abstract
- Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC <subscript>50</subscript> = 115.3 μM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3Kα H1047R mutant with an EC <subscript>50</subscript> value of 0.55 μM, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kα H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC <subscript>50</subscript> value of 10.9 μM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kα inhibitor.<br /> (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemical synthesis
Apoptosis drug effects
Cell Proliferation drug effects
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
Neoplasms drug therapy
Point Mutation
Protein Kinase Inhibitors chemical synthesis
Structure-Activity Relationship
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Phosphatidylinositol 3-Kinases genetics
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 158
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30245395
- Full Text :
- https://doi.org/10.1016/j.ejmech.2018.09.002