Designing bisubstrate analog inhibitors for protein kinases

Keykavous Parang, Philip A. Cole

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


Protein kinases play critical roles in signal transduction pathways by transmitting extracellular signals across the cell membrane to distant locations in the cytoplasm and the nucleus. The development of protein kinase inhibitors has been hindered by the broad overlapping substrate specificities exhibited by these enzymes. The design of bisubstrate analog inhibitors could provide for the enhancement of specificity and potency in protein kinase inhibition. Bisubstrate analog inhibitors form a special group of protein kinase inhibitors that mimic two natural substrates/ligands and that simultaneously associate with two regions of given kinases. Most bisubstrate analogs have been designed to mimic the phosphate donor (ATP) and the acceptor components (Ser-, Thr-, or Tyr-containing peptides). Recent studies have emphasized the importance of maintaining a specific distance between these two components to achieve potent inhibition. In this review, we present a discussion of the methods for designing protein kinase inhibitors by mechanism-based approaches. Emphasis is given to bivalent approaches, with an interpretation of what has been learned from more and less successful examples. Future challenges in this area are also highlighted.

Original languageEnglish (US)
Pages (from-to)145-157
Number of pages13
JournalPharmacology and Therapeutics
Issue number2-3
StatePublished - 2002
Externally publishedYes


  • Bisubstrate inhibitor
  • Insulin receptor kinase
  • Mechanism
  • Protein kinases
  • Src
  • Transition state

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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