Finding Inhibitors for a Cancer Target: CDK12 Activity Assays Accelerate the Search

All systems within our bodies function by means of proteins. When these proteins aren’t made correctly, our body malfunctions.  The short explanation: DNA is at the fabric of forming a functional protein; genes (made of DNA) get transcribed and then translated to become proteins. During this complex process, genes are not always correctly transcribed and the correct, working protein isn’t made. And, this is where cancer enters the story. Cancer is messy! There are numerous genes involved and multiple ways they can become mutated or silenced, leading to cancer.

It makes sense, that most of the mutated genes that contribute to cancer are involved in DNA replication, transcription, and gene expression. Cyclin-dependent kinases (CDK) are a family of serine/threonine protein kinases that regulate transcriptional and posttranscriptional processes. As transcription plays an important role in ensuring healthy individuals, certainly these proteins have the same objective.

Responsibility of CDK12 and Relationship to Cancer

As mentioned, genes have several opportunities to acquire mutations; consequently, our bodies have a DNA damage repair (DDR) system to prevent these threats. Studies have shown that CDK12 maintains genomic stability and expression of DDR genes.¹   Furthermore, tumors arise when aberrations in CDK12 are present.¹   Interestingly, microarray analysis shows that the deletion of CDK12 affect several genes including a decrease in BRCA1.¹

Aiding in a stable genome isn’t the only task of CDK12 as research has shown its involvement in development, transcription regulation, and splicing as well.² Even more exceptional, CDK12 appears to have both tumor-suppressive and tumorigenic properties according to research.² Nonetheless, studies have found that CDK12 inhibitors have decreased tumor growth and scientists want to continue finding similar solutions.²

CDK12 Activity Assays  

Although the protein kinase has many responsibilities, there is still much to learn regarding specific details into the exact functions and how alterations end in cancer. Measuring the activity of CDK12 is necessary when performing general research and for finding therapeutic strategies to fight against cancer in the case of CDK12 inhibitors.  Briefly, the nature of a protein kinase is to assist in the transfer of a phosphate from ATP to another molecule (or substrate), forming ADP as a product that can be measured by using specific antibody labeled with a fluorophore. A change in signal can then be used to measure enzymatic activity, screen for inhibitors, and perform SAR.

References

1. Lui GYL, Grandori C, Kemp CJ. CDK12: an emerging therapeutic target for cancer. J Clin Pathol. 2018;71(11):957-962. doi:10.1136/jclinpath-2018-205356
2. Paculová H, Kohoutek J. The emerging roles of CDK12 in tumorigenesis. Cell Div. 2017;12(1). doi:10.1186/s13008-017-0033-x