Development of Src
Kinase Inhibitors as Anticancer Agents
Src family kinases are
involved in the regulation of different cellular processes and in signal
transduction pathways. Considerable evidence implicates elevated
expression and/or activity of Src in cancer development. Activation of Src
is reported in many human cancers, including colon, breast, pancreas,
ovarian, lung, gastric, and head and neck. Thus, Src kinase is an
important target for anti-cancer drug discovery. The objective of our
research is to design selective and potent Src kinase inhibitors that can
have potential application for drug development. The specific purpose of
this proposal is to design Src kinase inhibitors that incorporate the best
features of several successful inhibitor design strategies, including
ATP-competitive inhibitors, peptide inhibitors, and structure-guided
design. We thus hypothesize that inhibitors that interact with multiple
sites in or near the active site of a kinase can produce synergistic
potency and specificity far better than single motif-based inhibitors. We
propose to optimize the lead compounds, determine the mechanisms of
inhibition, and expand this strategy to synthesize other analogs guided by
the same design principle. These studies are significant because they will
eventually lead to design of potent and selective Src kinase inhibitors,
as they allow a way to inhibit Src mediated signal transduction in cancer
cells.
