Small-molecule kinase inhibitors are being intensively pursued as new anticancer therapeutics. To date, approximately 80 inhibitors have been advanced to some stage of clinical evaluation.
Understanding the structural basis of kinase inhibitor selectivity is crucial to the ultimate goal of developing selective inhibitors to target every member of the kinome. Most currently known kinase inhibitors target the ATP binding site with the kinase activation loop in the active (type 1) or inactive (type 2) conformation.
New kinase inhibitors are primarily developed with a combination of methods, including high-throughput screening using biochemical or cellular assays, analogue synthesis, structure-guided design and fragment-based assembly strategies.
The repertoire of kinases targeted by a given inhibitor can be determined by profiling its activity in binding and enzymatic assays against extensive panels of recombinant kinases, by profiling activity in cellular assays and by affinity approaches integrated with detection by mass spectrometry.
Kinase inhibitor resistance resulting from selection for mutant alleles or upregulation of alternative signalling pathways is a recurrent theme in the clinic. Strategies for developing multiple inhibitors targeting different kinase sites and for discovering synergistic inhibitor combinations are urgently needed.
Deregulation of kinase activity has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. To date, 11 kinase inhibitors have received US Food and Drug Administration approval as cancer treatments, and there are considerable efforts to develop selective small molecule inhibitors for a host of other kinases that are implicated in cancer and other diseases. Herein we discuss the current challenges in the field, such as designing selective inhibitors and developing strategies to overcome resistance mutations. This Review provides a broad overview of some of the approaches currently used to discover and characterize new kinase inhibitors.
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Nathaneal Gray is a consultant for the Novartis Institute of Biomedical Research.
Kinases implicated in human cancer (PDF 265 kb)
The "DFG–in" conformation of EGFR (PDB ID 2J5F) with the covalent inhibitor 34–JAB (blue sticks) (PDF 143 kb)
Kinases in the different groups (PDF 103 kb)
Developing inhibitors of mutant Bcr–Abl kinase (PDF 210 kb)
National Cancer Institute Drug Dictionary
Protein Data Bank
- Synthetic lethal
Two genes have a synthetic-lethal phenotype if the individual gene deletions are not lethal but the combined mutation is. A synthetic-lethal interaction is proof of a genetic interaction.
An organic compound with a ring structure containing non-carbon atoms such as sulphur, oxygen or nitrogen as part of the ring.
A molecular framework that carries the essential features responsible for the biological activity of a drug.
- Allosteric site
A site distinct from the enzyme active site that can bind a ligand that either positively or negatively regulates enzyme activity.
A group of atoms that is rich in electrons and that participates in a chemical reaction by donating electrons to an electron-poor electrophile (electron lover).
A group of atoms that is deficient in electrons and that participates in a chemical reaction by accepting electrons from an electron-rich nucleophile (nucleus lover).
- Michael addition
Nucleophilic addition to an α,β-unsaturated carbonyl compound. It belongs to the larger class of conjugate additions.
Secondary metabolites from bacteria, fungi, plants and animals with diverse biological activities and pharmacological properties.
A chemical group with similar size and electronic properties.
- Homology model
A class of methods for constructing a three-dimensional structure of a target protein for which only the sequence is available, provided at least one empirical three-dimensional template structure with > 30% sequence identity is available.
Inhibitor concentration for half-maximum response.
Effector concentration for half-maximum response.
- Enrichment factor
The ratio of the number of biologically active compounds discovered using computationally based selection to the number found by random screening.
- Chemical space
The space spanned by all possible (that is, energetically stable) stoichiometrical combinations of electrons and atomic nuclei and topologies (isomers) in molecules and also compounds in general.
Two fused indole rings bridged by a maleimide that can act as an ATP-competitive kinase inhibitor.
- Steric clash
Atoms contain an electron shell with a defined radius that prevents atoms not engaged in a covalent bond from occupying the same volume. A steric clash occurs when two atoms are placed closer than the sum of their atomic radii.
- Farnesyltransferase activity
Post-translational modification of proteins that consists of attaching an isoprenyl group to a cysteine residue.
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Zhang, J., Yang, P. & Gray, N. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9, 28–39 (2009). https://doi.org/10.1038/nrc2559
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