Physicochemical and pharmacological determinants of the efficacy of a novel series of CDK7 inhibitors


Session type:

Maciej A Kaliszczak, Sebastian Kroll, Dean A. Heathcote, Simak Ali, Charles Coombes, Anthony GM Barrett, Matthew J Fuchter, Eric O Aboagye

Imperial College London, UK


Proffered paper presentation

CDK7 is a member of the cyclin-dependent protein kinase (CDK) family of protein kinases that play key roles in cell cycle progression. CDK7 phosphorylates other members of the CDK family including CDK2 and RNA polymerase II. CDK7 is abundantly expressed in cancers. Using a computer based approach, a novel series of CDK7 inhibitors was designed and synthesised. 20 compounds with nanomolar IC50 towards CDK7 were selected for further investigations. The aim of the current part of the project was to determine the physicochemical and pharmacological determinants of efficacy.

We first assessed membrane transport of the series using the caco-2 transwell assay and found that only compounds with PSA>85Ǻ2 were efficiently transported; Papp B-A / Papp A-B ratios >2. Compounds with pka<7.4 had low cellular permeability. This was not due to passive diffusion. Indeed, assessment of the potential interaction with ABC transporters (P-gp, ABCG2 and MRP1) identified the multi-drug resistance phenotype (MDR) as a key determinant of membrane transport. Again only compounds with PSA>85Ǻ2, were found to be substrates of P-gp and ABCG2. None appeared to be substrate of MRP1. In general the series was metabolically stable. The compounds were notably more stable in human S9/microsomes than in mouse (S9/microsomes) suggesting improved pharmacokinetics in humans. With regards structure activity relationships (SARs), nitrile derivatives and compounds with hydroxyls moieties were highly metabolized. Aromatic fluorine substitution per se appeared to inhibit metabolism. Furthermore, the position of the fluorine atom was important, with ortho derivatives being the most stable (p<0.001). The compounds are highly plasma protein bound although the SAR for plasma protein binding has not yet been determined.

In summary, we have identified physicochemical and pharmacological properties that predict potential in vivo efficacy of our CDK7 series. The studies will help refine the synthesis of more efficacious CDK7 inhibitors.