Discovery of Small Molecules that Inhibit the Disordered Protein, p27Kip1
Citations Over TimeTop 10% of 2015 papers
Abstract
Disordered proteins are highly prevalent in biological systems, they control myriad signaling and regulatory processes, and their levels and/or cellular localization are often altered in human disease. In contrast to folded proteins, disordered proteins, due to conformational heterogeneity and dynamics, are not considered viable drug targets. We challenged this paradigm by identifying through NMR-based screening small molecules that bound specifically, albeit weakly, to the disordered cell cycle regulator, p27(Kip1) (p27). Two groups of molecules bound to sites created by transient clusters of aromatic residues within p27. Conserved chemical features within these two groups of small molecules exhibited complementarity to their binding sites within p27, establishing structure-activity relationships for small molecule:disordered protein interactions. Finally, one compound counteracted the Cdk2/cyclin A inhibitory function of p27 in vitro, providing proof-of-principle that small molecules can inhibit the function of a disordered protein (p27) through sequestration in a conformation incapable of folding and binding to a natural regulatory target (Cdk2/cyclin A).
Related Papers
- → Switching Cdk2 On or Off with Small Molecules to Reveal Requirements in Human Cell Proliferation(2011)84 cited
- → 3D-QSAR CoMFA study on indenopyrazole derivatives as cyclin dependent kinase 4 (CDK4) and cyclin dependent kinase 2 (CDK2) inhibitors(2006)45 cited
- → Advances in synthesis and biological evaluation of CDK2 inhibitors for cancer therapy(2023)20 cited
- → Induction of differentiation accompanies inhibition of Cdk2 in a non-small cell lung cancer cell line.(1999)47 cited
- Comparative activity of the potent selective CDK2 inhibitor NU6102 in CDK2 wild-type and knock-out mouse embryo fibroblasts(2005)