2 research outputs found
ProteināLigand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase
The design of compounds that selectively inhibit a single
kinase
is a significant challenge, particularly for compounds that bind to
the ATP site. We describe here how proteināligand crystal structure
information was able both to rationalize observed selectivity and
to guide the design of more selective compounds. Inhibition data from
enzyme and cellular screens and the crystal structures of a range
of ligands tested during the process of identifying selective inhibitors
of FGFR provide a step-by-step illustration of the process. Steric
effects were exploited by increasing the size of ligands in specific
regions in such a way as to be tolerated in the primary target and
not in other related kinases. Kinases are an excellent target class
to exploit such approaches because of the conserved fold and small
side chain mobility of the active form
Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)
A novel series of small-molecule
inhibitors has been developed
to target the double mutant form of the epidermal growth factor receptor
(EGFR) tyrosine kinase, which is resistant to treatment with gefitinib
and erlotinib. Our reported compounds also show selectivity over wild-type
EGFR. Guided by molecular modeling, this series was evolved to target
a cysteine residue in the ATP binding site via covalent bond formation
and demonstrates high levels of activity in cellular models of the
double mutant form of EGFR. In addition, these compounds show significant
activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to
their observed clinical efficacy. A glutathione (GSH)-based assay
was used to measure thiol reactivity toward the electrophilic functionality
of the inhibitor series, enabling both the identification of a suitable
reactivity window for their potency and the development of a reactivity
quantitative structure-property relationship (QSPR) to support design