Abstract
SummaryDysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.
Highlights
Members of the cyclin-dependent protein kinase (CDK) family have diverse cellular roles that include regulation of the cell cycle and transcription and, in certain cell types, differentiation (Lim and Kaldis, 2013; Malumbres, 2014; Morgan, 2007)
ATP-Competitive Inhibitors Discriminate between Cyclin-free CDK1 and CDK2 Avoiding the inhibition of CDK1 in a multi-CDK or single-CDK inhibition strategy is complicated by the high degree of active site sequence identity within the CDK family, illustrated for CDKs 1 and 2 in Figure 1A (Figure S1)
To explore the potential for ATP-competitive inhibitors to discriminate between CDK1 and CDK2, five ATP-competitive CDK inhibitors (Figure 1B) were selected on the basis of their diverse pharmacophores and submicromolar half maximal inhibitory concentration (IC50) values toward CDK2-cyclin A and CDK1-cyclin B (Table S1)
Summary
Members of the cyclin-dependent protein kinase (CDK) family have diverse cellular roles that include regulation of the cell cycle and transcription and, in certain cell types, differentiation (Lim and Kaldis, 2013; Malumbres, 2014; Morgan, 2007). CCNE1 amplification or cyclin E1 overexpression has been described in a number of other cancers including osteosarcoma (Lockwood et al, 2011), breast (Karakas et al, 2016), and nonsmall-cell lung cancer (Freemantle and Dmitrovsky, 2010) Such ‘‘oncogene-addiction’’ to cyclin E occurs in a significant cohort of high-grade serous ovarian cancer (HGSOC) patients and confers a poor outcome to current therapy (Kanska et al, 2016; Kroeger and Drapkin, 2017; Patch et al, 2015). These findings suggest that a CDK2-selective inhibitor could be clinically beneficial in these cancer subtypes
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