Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition

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.

Integrative Bioinformatics Approaches to Map Potential Novel Genes and Pathways Involved in Ovarian Cancer

“…Many studies have suggested that CDK2 could be a crucial factor in the progression of cancer by regulating several pathways and might be a prospective biomarker and indicator of prognosis. Therefore, CDK2 and its cyclin binding partners are possible therapeutic targets for future cancer treatments (Yin et al, 2018;Zhang et al, 2018;Wood et al, 2019).…”

Plant β-tubulin phosphorylation on Ser172 as canonical suppressing factor of microtubule growth

“…The 3D-models of protein kinases were constructed with the Swiss-Model web-service [18]. The structural model of plant cyclin-dependent kinase 1 (CDKA1_ARATH, UniProtKB: P24100) was constructed using RCSB ProteinDataBank tamplate structure 6gu7 (X-Ray diffraction, 2.75 Е) of human cyclin-dependent kinase 1 [19]. The structural model of plant Cdk 1 from S. cerevisiae (CDK1_YEAST, UniProtKB: P00546) was also constructed using structure 6gu7 [19].…”

“…The structural model of plant cyclin-dependent kinase 1 (CDKA1_ARATH, UniProtKB: P24100) was constructed using RCSB ProteinDataBank tamplate structure 6gu7 (X-Ray diffraction, 2.75 Е) of human cyclin-dependent kinase 1 [19]. The structural model of plant Cdk 1 from S. cerevisiae (CDK1_YEAST, UniProtKB: P00546) was also constructed using structure 6gu7 [19]. The structural model of YAK1-related kinase (UniProtKB: Q8RWH3) from A. thaliana was taken from our previous research [20].…”

Novel [(N-alkyl-3-indolylmethylene)hydrazono]oxindoles arrest cell cycle and induce cell apoptosis by inhibiting CDK2 and Bcl-2: synthesis, biological evaluation and in silico studies

“…This dimeric scaffold is initiative for the design of other derivatives with a significant activity against CDKs as reported 8 , 9 . Other isatin derivatives decorated with 3-substitution expressed potent inhibition for CDK2 as shown in SU9516 which inhibits CDK2 with IC 50 = 25 nM ( Figure 1 ) 10 . Moreover, compound ( I ) is another isatin derivative with hydrazino linker at position 3 (CDK2; IC 50 = 60 nM) that was co-crystallized with its target and submitted to protein data bank (1VFT).…”