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Published on: May 3, 2018
Computational identification and experimental characterization of an aurora kinase inhibitor
Muhammad Muddassar1, Muhammad Furqan2, Numan Yousaf1
1Department of Biosciences, COMSATS University Islamabad, Park Road, Islamabad, Pakistan.
Abstract:
The serine/threonine kinases of the aurora family are critical for completing various stages of mitotic cell division. They are frequently overexpressed in various cancers, associated with poor prognosis, and have been validated as an attractive drug target. Despite promising preclinical results, the clinical development of small molecule inhibitors targeting aurora kinases is often hampered by limited efficacy as single agents and severe side effects. Recent discoveries of the synthetic interaction of aurora A with various tumor suppressors and its involvement in the development of resistance to third-generation EGFR inhibitors have renewed interest in finding aurora kinase inhibitors. This study utilized computational approaches to discover an aurora kinase inhibitor. Chemical features of two structurally distinct inhibitors of aurora kinase were exploited to develop a molecular shape and color-based model for the virtual screening of small synthetic molecules in the Enamine database. Six hit compounds validated through docking and Molecular Dynamics (MD) simulation studies were evaluated in a cell-based assay. Only MC-688 inhibited both aurora kinases (A and B) and bound to both kinases in a competition binding assay. Analysis of STD-NMR and 2D NOESY spectra confirmed the computationally predicted binding mode of MC-688 with the ATP binding pocket of aurora A. MC-688 inhibited cell proliferation and long-term treatment of HCT116 colorectal cancer cells with MC-688 induced abrogated mitosis, ultimately leading to apoptotic cell death. In conclusion, MC-688 was computationally identified and experimentally validated as a new pan-aurora inhibitor that induces aurora phenotype in cells and can be used as a lead for further optimization.
Insights
Researchers discovered MC-688, a new inhibitor targeting aurora kinases (A and B), crucial for cell division and cancer. This compound shows promise for cancer therapy by halting cancer cell proliferation and inducing cell death.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Aurora kinases are key regulators of mitotic cell division.
- Overexpression of aurora kinases is linked to various cancers and poor prognosis, making them attractive drug targets.
- Existing aurora kinase inhibitors face challenges with efficacy and side effects in clinical development.
Purpose of the Study:
- To computationally discover and experimentally validate a novel inhibitor targeting aurora kinases.
- To identify a compound that can overcome limitations of current aurora kinase inhibitors.
Main Methods:
- Development of a molecular shape and color-based model for virtual screening using Enamine database.
- Docking and Molecular Dynamics (MD) simulations for hit compound validation.
- Cell-based assays, competition binding assays, STD-NMR, and 2D NOESY to confirm binding and mechanism of action.
Main Results:
- Six hit compounds were identified through virtual screening and validated computationally.
- MC-688 was identified as a potent inhibitor of both aurora kinase A and B.
- MC-688 demonstrated inhibition of cancer cell proliferation and induced apoptotic cell death in HCT116 cells.
- Experimental data confirmed the predicted binding mode of MC-688 to the aurora A ATP binding pocket.
Conclusions:
- MC-688 was computationally identified and experimentally validated as a novel pan-aurora kinase inhibitor.
- MC-688 effectively inhibits cancer cell proliferation and induces apoptosis, presenting a potential therapeutic lead.
- Further optimization of MC-688 could lead to improved cancer treatments targeting aurora kinases.
