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Taking Quinazoline as a General Support‐Nog to Design Potent and Selective Kinase Inhibitors: Application to FMS‐like Tyrosine Kinase 3

The dramatic success of the first approved protein kinase inhibitor imatinib (Gleevec) for the treatment of chronic myelogenous leukemia has fueled an explosion in kinase inhibitor research in both the pharmaceutical industry and academia. However, due to the large size of the protein kinase superfamily and the fact that most kinase inhibitors bind in the highly conserved ATP binding pocket, it is extremely difficult to impart selectivity to kinase inhibitors. This has been the most challenging problem in the discovery and development of drugs that target protein kinases. Over the past decade, significant efforts have been devoted to address this problem. Even so, a very limited number of specific kinase inhibitors have been identified at present. Herein we report a very simple and efficient strategy to design selective kinase inhibitors. This strategy is then applied to the design of FMS-like tyrosine kinase 3 (FLT3) inhibitors. The basic idea of this strategy originates from an observation of chemical structures and binding modes of some known kinase inhibitors. Currently there are nine kinase inhibitors approved as marketed drugs by the US Food and Drug Administration (FDA; see figure S1 in the Supporting Information). Three of them are 4-anilinoquinazoline derivatives, namely gefitinib (Iressa), erlotinib (Tarceva), and lapatinib (Tykerb). These inhibitors adopt very similar binding modes in the active sites of their respective target kinases: the quinazoline ring is located at the front of the ATP binding pocket, where it is sandwiched between two loops in the Nand C-lobes of the catalytic domain. Furthermore, it is consistently oriented with its N1 atom hydrogen bonded to an amide group in the so-called “hinge” region of the kinase, which connects the Nand Clobes. 4-Aniline substituents, at various angles with respect to the quinazoline ring plane, match the hydrophobic pocket at the back of the ATP binding cleft. The 6and 7-substituents of the quinazoline ring extend into the solvent and are generally poorly ordered; these positions are often modified for the purpose of improving the pharmacokinetic properties of the inhibitors. To examine whether this binding mode of 4-anilinoquinazoline-type kinase inhibitors is universally adopted in other kinases, we collected all the 4-anilinoquinazoline-type inhibitor– kinase complex structures available from the Protein Data Bank (PDB; see figure S2 in the Supporting Information). Figure 1 a shows an aligned superposition of these crystal structures,