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Development of 2'-aminospiro [pyrano[3,2-c]quinoline]-3'-carbonitrile derivatives as non-ATP competitive Src kinase inhibitors that suppress breast cancer cell migration and proliferation.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2021 Nov; Vol. 116, pp. 105344. Date of Electronic Publication: 2021 Sep 20. - Publication Year :
- 2021
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Abstract
- Src kinase activity controls diverse cellular functions, including cell growth, migration, adhesion, and survival. It is de-regulated in several cancers, including breast cancer, where it is highly expressed and phosphorylated. Thus, targeting Src by a small molecule is a feasible strategy for managing different breast cancer types. Several Src kinase inhibitors are available, including the FDA-approved drug (dasatinib). However, they are primarily ATP-competitive inhibitors that have been reported to lack specificity towards Src. We have a long-time interest in discovering protein kinase inhibitors that are non-competitive for ATP. In this project, three groups of 2'-aminospiro[pyrano[3,2-c]quinoline]-3'-carbonitrile derivatives were designed and synthesized, hypothesizing that small molecules with a spiro scaffold appended to a pyrano[3,2-c]quinoline analog could act as non-ATP competitive Src kinase inhibitors. 3b, 3c, and 3d inhibited Src kinase activity with IC50s of 4.9, 5.9, and 0.9 μM, respectively. At the same time, they did not impact the MDM2/p53 interaction in HEK293 cells, which has been reported to be affected by some spirocyclic compounds. 25 µM of 3b, 3c, or 3d did not inhibit the kinase activity of ERK2, JNK1, or p38-alpha in an in-vitro kinase assay. Steady-state kinetic studies for the effect of 3d on the ability of recombinant Src to phosphorylate its substrate (Srctide) revealed a non-ATP competitive inhibition mechanism. 1.6 µM of 3d was enough to diminish Src, Fak, and paxillin phosphorylation in the breast cancer cell lines MDA-MB-231 and MCF7. In the NCI screening, 3d induced broad tumor cytotoxicity for the NCI-60 cell lines, including all the breast cancer cell lines. The potency of 3b, 3c, and 3d to inhibit migration, proliferation, and colony formation of MDA-MB-231 and proliferation of MCF7 cells correlates with their potency to suppress Src kinase activity in the same cell line. Noticeably, the cell growth suppression and apoptosis induction in the tested cell lines can be attributed to the ability of the new derivatives to suppress the ERK and Akt survival pathways downstream of Src.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Breast Neoplasms metabolism
Breast Neoplasms pathology
Cell Line, Tumor
Cell Movement drug effects
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HEK293 Cells
Humans
Molecular Structure
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Pyrans chemical synthesis
Pyrans chemistry
Quinolines chemical synthesis
Quinolines chemistry
Structure-Activity Relationship
src-Family Kinases metabolism
Antineoplastic Agents pharmacology
Breast Neoplasms drug therapy
Drug Development
Protein Kinase Inhibitors pharmacology
Pyrans pharmacology
Quinolines pharmacology
src-Family Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 116
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34598088
- Full Text :
- https://doi.org/10.1016/j.bioorg.2021.105344