Cyclin-dependent kinase 7 (CDK7) exhibits an interesting target for an anti-cancer therapy approach. CDK7’s triple role in phosphorylation (cell cycle, transcription, estrogen receptor (ER)) in cell regulation makes this kinase interesting. Phosphorylation of cell cycle CDK’s via its CAK-complex, of Ser-5 in RNA-PolII as part of the TFIIH-complex and phosphorylation of Ser-118 in ER all show the importance of this enzyme. Given that CDKs are over-expressed in many cancers, selective inhibition of CDK7 should result in cell cycle arrest and apoptosis predominately in tumour cells. Previously, BS-181 (Figure 0.1) has been reported as the first CDK7 selective inhibitor, which displayed a good in vitro and in vivo profile.1 Based on this initial lead compound, a library of rational-designed analogues was synthesised. Much of this library was based on a computer-aided-drug-design (CADD) approach by docking, which gave valuable insights in possible binding modes and helped to focus targeting the whole active site. [Molecular structure diagrams appear here. To view, please open pdf attachment] Figure 0.1: BS-181 and new analogues. Several of these novel inhibitors showed excellent selectivity versus CDK2 in particular, and potency against CDK7 in the 30 – 60 nM range for their IC50-values. Cellular assays confirmed the growth inhibitory properties of these new compounds, with GI50-values in the low μM range. This work also demonstrates what functional groups were tolerated in the 3-,5- and 7-position.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:575993 |
| Date | January 2011 |
| Creators | Kroll, Sebastian Herbert Benjamin |
| Contributors | Barrett, Anthony |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/11657 |
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