br Additional CDKs with a role in
Additional CDKs with a role in cancer
Small molecule CDK inhibitors The majority of protein kinase inhibitors developed to date are type I inhibitors: they bind at the ATP–binding site, are ATP-competitive and target the kinase in its active state; with the activation loop DFG motif in the ‘in’ position. In contrast, type II inhibitors can bind kinases that are in an inactive conformation, with the DFG motif flipped ‘out’. In addition to binding the ATP binding site, Type II inhibitors can also occupy a hydrophobic site, made accessible by the flipped “out” conformation of the DFG motif. Type II inhibitors are believed to be more selective than Type I inhibitors, however for both type of compounds there are examples of both highly selective and non-selective inhibitors (Treiber & Shah, 2013). The development of selective CDK/cyclin inhibitors was initially thought to be challenging since it was commonly believed that Fmoc-Thr(tBu)-OH sale binding prevented the conformational change required at the ATP-binding site to generate a type II inhibitor-binding pocket, thus restricting the inhibitors to type I binding modes. In addition, the high degree of similarity between the ATP-binding sites of the CDKs was also predicted to be a challenge to generating isoform-selective inhibitors. Consistent with this the early type I inhibitors were generally found to be promiscuous across multiple CDKs. However, as described in this review it is now clear that it is possible to identify and develop potent CDK-selective type I inhibitors and also inhibitors that bind with a type II binding mode. The first CDK inhibitors were developed predominantly against CDK2 and were relatively unselective, but acted as early pathfinder agents. These inhibitors encompassed heteroaromatic scaffolds including flavonoid, purine, indenopyrazole, aminopyrimidine, aminothiazole, indirubin, hymenialdisine, and paullone derivatives (Asghar et al., 2015, Sanchez-Martinez et al., 2015). Below we describe the early pan-CDK inhibitors and the improvements that have led to the current clinical studies with multi-target CDK inhibitors. We also discuss recent exciting advances in the development of isoform-selective CDK inhibitors.
Conclusion and outlook A real shift in attitude about the clinical use of CDK inhibitors has been the progression the CDK4/6-selective, ATP-competitive inhibitors palbociclib, abemaciclib and ribociclib – which are either approved or in advanced registration trials for several cancers. The discovery and clinical development of these drugs, and in particular, the FDA approval for palbociclib in ER+ breast cancer, has revived serious interest in inhibitors of the cell cycle CDKs. The identification and development of selective CDK4/6 inhibitors is a major breakthrough in the treatment of metastatic breast cancer and their activity in other cancer types will be defined by the outcomes of ongoing clinical trials. In addition, the identification of tolerated and active combination regimes, patient stratification biomarkers and resistance mechanisms will contribute to our greater understanding of their potential use. Furthermore, the utility of CDK4/6 inhibition in preventing the emergence of resistance to multiple targeted therapies across various cancer types is an area of intense clinical investigation, results of which are eagerly anticipated (www.clinicaltrials.gov) (Gao et al., 2015). The selective CDK4/6 inhibitors are exemplars for inhibitors of other CDKs targets where the identification of highly selective compounds with pharmaceutical properties is critical. Strategies exploring alternative and non-competitive approaches to CDK inhibition – such as allosteric, covalent binding and peptidomimetic mechanisms – may uncover novel pharmacology and expand the therapeutic utility of these agents. For example, MMD37K (Sanchez-Martinez et al., 2015), a peptidomimetic derived from p16, is the first alternative class of CDK4/6 inhibitor to enter clinical studies and the data generated will allow comparisons with existing ATP-competitive inhibitors.