Inhibitor Trapping in Kinases

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Recently, we identified a novel mechanism of enzyme inhibition in N-myristoyltransferases (NMTs), which we have named ‘inhibitor trapping’. Inhibitor trapping occurs when the protein captures the small molecule within its structural confines, thereby preventing its free dissociation and resulting in a dramatic increase in inhibitor affinity and potency. Here, we demonstrate that inhibitor trapping also occurs in the kinases. Remarkably, the drug imatinib, which has revolutionized targeted cancer therapy, is entrapped in the structure of the Abl kinase. This effect is also observed in p38α kinase, where inhibitor trapping was found to depend on a ‘magic’ methyl group, which stabilizes the protein conformation and increases the affinity of the compound dramatically. Altogether, these results suggest that inhibitor trapping is not exclusive to N-myristoyltransferases, as it also occurs in the kinase family. Inhibitor trapping could enhance the binding affinity of an inhibitor by thousands of times and is as a key mechanism that plays a critical role in determining drug affinity and potency.
Funding Information
  • European Union-NextGenerationEU through the National Recovery and Resilience Plan of the Republic of Bulgaria (BG-RRP-2.004-0004-C01, BG05M2OP001-1.001-0003)
  • Science and Education for Smart Growth Operational Program (BG-RRP-2.004-0004-C01, BG05M2OP001-1.001-0003)
  • European Union through the European Structural and Investment Funds (BG-RRP-2.004-0004-C01, BG05M2OP001-1.001-0003)

This publication has 54 references indexed in Scilit: