in proliferation assays. It is interesting to note that all of the type II inhibitors that have been found to effectively target ABL Thr315Ile, to date, are less selective than imatinib or nilotinib. The success of dasatinib as a second generation therapy for the treatment of imatinib resistant CML SKI-606 Bosutinib shows that a compound with a limited selectivity profile can still serve as an effective drug. Resistance to Inhibitors of EGFR The epidermal growth factor receptor is a cell surface receptor tyrosine kinase in the larger ErbB family of receptors. Upon binding of the epidermal growth factor, EGFR transitions from an inactive monomeric form to an active homo or heterodimer to initiate intracellular signaling that results in cell growth, migration, differentiation and death.
Mutations that occur in the EGFR kinase domain that cause the kinase to be over expressed or hyperactive have been implicated in the development of cancer, particularly non small cell Krishnamurty and Maly Page 5 ACS Chem Biol. Author manuscript, available in PMC 2011 January 15. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript lung carcinomas . To this end, AZD8055 a number of reversible ATP competitive smallmolecule kinase inhibitors have been developed to target EGFR. These inhibitors include the clinically approved 4 anilinoquinazolines gefitinib , erlotinib and lapatinib and the clinical candidate AEE788 . In addition to inhibitors that interact with the ATP binding site of EGFR in a reversible manner, several analogs that covalently modify the active site have been developed.
An example of an inhibitor of this class is the 4 anilino 3 quinolinecarbonitrile inhibitor neratinib, which covalently modifies Cys797 in the ATP binding site of EGFR. Gefitinib, erlotinib and lapatinib are structurally related quinazoline based compounds that display different anilines from the 4 position. These inhibitors interact with the ATP binding pocket of EGFR in a similar manner, with the quinazoline core positioning itself along the hinge region. This orientation allows the nitrogen from the quinazoline core to form a hydrogen bond with the hinge region and the substituents at the 6 and 7 position to extend into the solvent.
The small threonine gatekeeper residue of EGFR allows the aniline at the 4 position to form extensive interactions with the hydrophobic pocket adjacent to the adenine site, which contributes to the high selectivity exhibited by these compounds. Lapatinib, which contains a more extended 4 anilino substituent than erlotinib and gefitinib, binds to a unique inactive conformation of EGFR. Kinome wide selectivity screens have demonstrated that these inhibitors are highly selective for EGFR and its ErbB family members, with lapatinib showing the highest selectivity. The reversible inhibitor AEE788 binds to EGFR kinase in the active conformation, with the C helix pointing in towards the ATP binding pocket. Much like the quinazoline inhibitors, the pyrrolopyrimidine core of AEE788 makes hydrogenbonding interactions with the backbone amides of the kinase hinge region. Mimicking the aniline groups of gefitinib and erlotinib, the phenethylamine substituent extends into a hydrophobic pocket guarded by the gatekeeper residue, while the ethylpiperazine moiety is directed out of the ATP binding pocket, towards the s