Introduction to my KCGS CDK family project

At the SGC-UNC we are interested in building a set of inhibitors that “covers” the whole kinome. Here’s a reference that talks about our plans for the Kinase Chemogenomic Set (KCGS): http://journals.plos.org/plosone/article/related?id=10.1371/journal.pone.0181585. We are building the set with what we call “narrow spectrum” inhibitors – inhibitors that inhibit only a small set of kinases.

To help build this set I am looking at the CDK and CDK-like families of kinases. It’s a pretty big family, but many of the kinases in it have not gotten much attention. SNS-032 is a CDK2 inhibitor that advanced into clinical trials, so it has clearly has some good properties. We are interested in it because there is data that shows that it binds to several targets other than CDK2 that are not so well studied. The data comes from a great paper (https://www.ncbi.nlm.nih.gov/pubmed/22037378) by Ambit (now Discoverx) and can be found here: http://lincs.hms.harvard.edu/db/datasets/20171/ (By the way, this Harvard LINCS site is a great place to look for kinase data).

Here are the results that got us interested in exploring this scaffold.

CDKL2 = 41 nM

CDKL5 = 1.7 nM

CDK7 = 31 nM

CDK11A (CDC2L2) = 48 nM

CDK13 (CDC2L5) = 23 nM

CDK16 (PCTK1) = 7.1 nM

CDK17 (PCTK2) = 13 nM

CDK18(PCTK3) = 44 nM

If you search on these gene names in pubmed, you can see that there are not that many publications around these targets (see table below). This is not a perfect way to look at how much a target has been studied, but it can give you a good feel. With almost 700 references, it is clear CDK2 has received a lot of attention. I added EGFR as another example of a very popular kinase.

CDKL2: 16 references

CDKL5: 80 references

CDK7: 169 references

CDK11A: 59 references

CDK13: 44 references

CDK16: 56 references

CDK17: 31 references

CDK18: 35 references

CDK2: 696 references

EGFR: 4584 references

I have started making analogues of SNS-032 and I will get them screened against these understudied off-targets. I hope to find ways to improve the potency and selectivity and create useful tools so we can understand the functions of these kinases.

For starters, I am using the published chemistry routes and making changes to the amide group. I will also move on to investigate the thiazole core and the oxazole piece as well.

In the coming weeks I’ll show you the chemistry schemes, successes, problems, and the building blocks I’ve picked. Screening data will come after that! Feel free to suggest other ideas. If you have any questions or comments or want more detail on anything, please let me know.