Targeting cancer with small molecule kinase inhibitors

Abstract

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.

Figure 1 |. Kinase inhibitor binding modes.

Kinase inhibitor–protein interactions are depicted by ribbon structures (left) and chemical structures (right). The chemical structures depict hydrophobic regions I and II of ABL1 (shaded beige and yellow respectively) and hydrogen bonds between the kinase inhibitor (inhibitor atoms engaged in hydrogen bonds to hinge are highlighted in green or to allosteric site in red) and ABL1 are indicated by dashed lines. The DFG motif (pink), hinge and the activation loop of ABL1 are indicated in the ribbon representations. The kinase inhibitors are shown in light blue. a | ABL1 in complex with the type 1 ATP-competitive inhibitor PD166326 (Protein Data Bank (PDB) ID 1OPK). Shown here is the DFG-in conformation of the activation loop (dark blue). b | The DFG-out conformation of the activation loop of ABL1 (dark blue) with the type 2 inhibitor imatinib (PDB ID 1IEP). The allosteric pocket exposed in the DFG-out conformation is indicated by the blue shaded area (right).

Figure 2 |. Diverse kinase inhibitors.

The ATP binding site of AKT1 complexed with ATP (Protein Data Bank (PDB) ID 1O6L) is depicted with key regions indicated and hydrogen bonds indicated by red dotted lines. The middle ring shows commonly used heterocyclic core scaffolds (X = C, N). The outer ring shows examples of structurally diverse type 1 inhibitors and their reported kinase targets. Hydrogen bonds are indicated by hashed lines on these structures. EGFR, epidermal growth factor receptor; Eph, ephrin receptor tyrosine kinases; FAK, focal adhesion kinase; PDGFR, platelet-derived growth factor; PLK, Polo-like kinase; VEGFR, vascular endothelial growth factor receptor.

Figure 3 |. Allosteric kinase activity modulators.

a | The figure shows the chemical structures of MEK1 inhibitors. AZD-6244 and PD334581 are second-generation MEK1 inhibitors, currently under clinical development. b | CI-1040 (indicated by a blue circle) binds MEK1 (green ribbon, Protein Data Bank (PDB) ID 1S9J) immediately adjacent to the ATP binding site (indicated by red circle). c | GNF2 binds the myristate binding site of BCR (breakpoint cluster region)–ABL1, which is located at the carboxyl terminal of the kinase domain. ON012380 is a non-ATP-competitive inhibitor of BCR–ABL1 that appears to be substrate site competitive. The binding site of the Akt inhibitors is unknown, but the pleckstrin homology domain of Akt is required for activity. The binding site for the inhibitor BMS-345541 on inhibitor of nuclear factor-κB kinase (IKK) is uncharacterized.

Figure 4 |. Representative irreversible inhibitors and locations of cysteines that are accessible for covalent modification across the kinome.

a | The ribbon structure depicts the cysteine-containing interleukin 2 tyrosine kinase (Protein Data Bank (PDB) ID 1SM2). A structure-guided bioinformatics analysis based on the available literature was conducted to identify all protein kinases with a cysteine residue that could potentially be targeted by an ATP binding site inhibitor revealed that more than 200 kinases (approximately 40% of the protein kinome) have such a cysteine. The kinases were classified according to the position of the cysteine residue in the active site. Group 1 kinases harbour such cysteines in the glycine-rich-loop (also known as the P-loop; shown in dark blue), which forms the ‘roof’ of the ATP binding site. In group 2 kinases, the cysteine is located within the three amino acids shown in pink directly after the glycine-rich loop. The cysteine in group 3 kinases (yellow) is located within the amino acids that constitute the hinge connecting the amino- and carboxy-terminal kinase lobes. These precede the DFG motif (pink), marking the start of the kinase activation loop (not visible in the X-ray structure because it is disordered) in which the cysteine residue that is modified in group 4 kinases (shown in dark blue) is located. b | Chemical structures of reported covalent inhibitors that react with the cysteine group are indicated. Green shading indicates inhibitor atoms involved in hydrogen bonding to the kinase hinge. The complete list of the kinases in the different groups is provided in Supplementary Information S3 (box). EGFR, epidermal growth factor receptor; RSK, ribosomal S6 kinase; VEGFR, vascular endothelial growth factor receptor.