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

Drug Discovery: Towards the Synthesis of Novel CDK2-Spy1 Inhibitors

As vital regulatory proteins in the cell cycle, cyclin-dependent kinases (CDKs) and cyclins ensure normal cell division and growth by monitoring check points in the cell cycle. CDKs are inactive on its own, but when a cyclin binds to CDK the activated CDK-Cyclin complexes then carry out their role as cell cycle regulators. Unregulated CDK-Cyclin complexes cause cells to grow and divide at a premature stage, and that can lead to uncontrolled cell growth. Existing treatments such as CKI (cyclin-dependent kinase inhibitor) therapy have cytotoxicity issues because of their inability to differentiate cancer cells from healthy cells, resulting in unwanted side effects. Our collaborators in the Porter Lab have identified a new target: CDK2-Spy1 complex. Spy proteins are alternative activators to CDKs in cancer cells, but not in healthy cells, making them an ideal therapeutic target. Notably, the Spy1 gene is among the top 50 genes associated with carcinoma, yet the CDK2-Spy1 complex has never been selectively targeted before in terms of CKI therapy. We therefore aim to synthesize molecules that selectively target CDK2-Spy1 complexes to develop a chemotherapy that has minimal cytotoxicity issues. In this presentation I will discuss our current progress towards small molecule inhibitors that show promising selectivity for CDK2-Spy1 complexes based on computational studies. Our synthetic routes and the analytical techniques employed to characterise these compounds will be described

The Synthesis of Natural Tn Antigen Carbohydrate Vaccines

The Synthesis of Natural Tn Antigen Carbohydrate Vaccines Aiyireti (Dina) Dilinaer, Michael R. Reynolds, S. Iraj Sadraei, John F. Trant The immune system plays an important role in defending the human body against diseases and invasion of pathogens. When the immune system fails to recognize and kill the pathogen or mutated cells, diseases such as cancer will develop and spread in the body. As an antigen that is produced by many types of cancer cells, the Tn antigen was discovered 60 years ago and has been of interest to synthetic organic chemists ever since. Despite the fact that it has never been found on healthy cells, the immune system does not detect it as foreign and therefore, does not trigger an immune response. Even though it has a simple structure of a monosaccharide linked to an amino acid, it is very difficult to isolate from biological systems and the present method of obtaining this natural antigen is extremely costly. The chemical structure of the Tn antigen also makes it unstable in the human body since it could be broken down by glycosidases, resulting in great difficulty studying it’s properties in vivo. Therefore, it is the Trant Team’s goal to synthesize two chemical derivatives of the Tn antigen which are more stable and will be able to elicit an immune response. Namely, we are working toward the development of immunotherapeutic cancer vaccines that could not only slow down the progression of diseases, but may inhibit the formation of certain carcinomas altogether. Once the derivatives are made on a larger scale, studies will be done both in vitro and in vivo to compare its stabilities and functionalities with the “acetal-free” analogues of the antigen