Physicochemical properties of novel protein kinase inhibitors in relation to their substrate specificity for drug transporters

Expert Opin Drug Metab Toxicol. 2015 May;11(5):703-17. doi: 10.1517/17425255.2015.1006626. Epub 2015 Jan 29.


Introduction: Small molecule tyrosine and serine-threonine kinase inhibitors (TKIs and STKIs) are emerging drugs that interfere with downstream signaling pathways involved in cancer proliferation, invasion, metastasis and angiogenesis. The understanding of their pharmacokinetics, the identification of their transporters and the modulating activity exerted on transporters is pivotal to predict therapy efficacy and to avoid unwarranted drug treatment combinations.

Areas covered: Experimental or in silico data were collected and summarized on TKIs and STKIs physico-chemical properties, which influence their transport, metabolism and efficacy, and TKIs and STKIs as influx transporter substrates and inhibitors. In addition, the uptake by tumor cell influx transporters and some factors in the tumor microenvironment affecting the uptake of TKIs and STKIs by cancer cells are briefly covered.

Expert opinion: Membrane transporters play an important role in the pharmacokinetics and hence the efficacy of anticancer drugs, including TKIs and STKIs. These drugs are substrates and inhibitors of various transporters. Drug resistance may be bypassed not only by identifying the proper transporter but also by selective combinations, which may either downregulate or increase transporter activity. However, care has to be taken because this profile might be disease, drug and patient specific.

Keywords: efflux transporters; influx transporters; physicochemical properties; serine-threonine kinase inhibitors; tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Biological Transport
  • Drug Resistance, Neoplasm
  • Humans
  • Membrane Transport Proteins / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects
  • Substrate Specificity
  • Tumor Microenvironment


  • Antineoplastic Agents
  • Membrane Transport Proteins
  • Protein Kinase Inhibitors