Tyrosine kinase inhibitors: rationale, mechanisms of action, and implications for drug resistance.
Tyrosine kinases play a role in normal cellular regulatory processes. However, aberrant tyrosine kinase activity can lead to cellular transformation and can be causally associated with tumor maintenance and progression. In the last few years, high-throughput screening and the use of combinatorial, computational, and medicinal chemistry have led to the identification of small molecules that compete with the adenosine triphosphate binding site of the catalytic domain of several oncogenic tyrosine kinases. Some of these compounds are highly specific to a single tyrosine kinase, while others can inhibit several homologous kinase pockets simultaneously. At a practical level, the relative promiscuity of these inhibitors against more than one oncogenic tyrosine kinase may have clinical merit as well as implications for host tissue toxicity. Many of these small molecules are in different stages of preclinical and clinical development against several solid tumors and will be discussed.
Busse
D
D
Departments of Medicine and Cell Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Yakes
F M
FM
Lenferink
A E
AE
Arteaga
C L
CL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases