Author ORCID Identifier

0000-0003-4922-0381

Standing

Graduate (PhD)

Type of Proposal

Oral Research Presentation

Faculty

Faculty of Science

Faculty Sponsor

Dr. John F. Trant

Abstract/Description of Original Work

The cell cycle of a healthy eukaryotic cell depends on the efficiency of cyclin-dependent kinase (CDKs) checkmarks, to ensure normal cell proliferation. CDK2 is responsible for progression of cells into the S and M phases, and it is critical to the abnormal growth processes of cancer cells. Examination of different kinds of human cancers, for their vulnerability to CDK2 inhibition, has revealed CDK2 as a good therapeutic target. In the past two decades, various CDK2 inhibitors have been designed but have stumbled on the roadblock of selectivity issue, since CDK2 shares 74 and 68% sequence identity and active sites with its family members’ CDK3 and CDK1, respectively. Moreover, it’s not CDK2 alone that needs to be targeted but the activated complex it forms with Spy1, a protein that can activate CDK2 in the same way as cyclin but is highly upregulated in cancer cells. After extensive computational studies, we found some unique yet challenging CDK2/SPY1 inhibitors.

In this presentation, I will discuss the importance of stereochemical control in the design and synthesis of novel and selective CDK2/SPY1 inhibitors. The synthesis ensures that the inhibitors are stereochemically pure, and thus the biological activity can be accurately evaluated. These results can then be used to refine our computational models to further improve the selectivity of our drug candidates.

Availability

March 29, From 12-4 pm

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Synthesis of Selective CDK2/SPY1 Inhibitors employing Stereochemical Control - An invaluable tool in an Organic Chemist’s belt

The cell cycle of a healthy eukaryotic cell depends on the efficiency of cyclin-dependent kinase (CDKs) checkmarks, to ensure normal cell proliferation. CDK2 is responsible for progression of cells into the S and M phases, and it is critical to the abnormal growth processes of cancer cells. Examination of different kinds of human cancers, for their vulnerability to CDK2 inhibition, has revealed CDK2 as a good therapeutic target. In the past two decades, various CDK2 inhibitors have been designed but have stumbled on the roadblock of selectivity issue, since CDK2 shares 74 and 68% sequence identity and active sites with its family members’ CDK3 and CDK1, respectively. Moreover, it’s not CDK2 alone that needs to be targeted but the activated complex it forms with Spy1, a protein that can activate CDK2 in the same way as cyclin but is highly upregulated in cancer cells. After extensive computational studies, we found some unique yet challenging CDK2/SPY1 inhibitors.

In this presentation, I will discuss the importance of stereochemical control in the design and synthesis of novel and selective CDK2/SPY1 inhibitors. The synthesis ensures that the inhibitors are stereochemically pure, and thus the biological activity can be accurately evaluated. These results can then be used to refine our computational models to further improve the selectivity of our drug candidates.