2 research outputs found
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
Discovery of Pyrazolo[1,5â<i>a</i>]pyrimidine BâCell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors
Inhibition of the proteinâprotein
interaction between B-cell
lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic
target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling
of potent and selective BCL6 inhibitors are critical to test this
hypothesis. We identified a pyrazoloÂ[1,5-<i>a</i>]Âpyrimidine
series of BCL6 binders from a fragment screen in parallel with a virtual
screen. Using structure-based drug design, binding affinity was increased
100000-fold. This involved displacing crystallographic water, forming
new ligandâprotein interactions and a macrocyclization to favor
the bioactive conformation of the ligands. Optimization for slow off-rate
constant kinetics was conducted as well as improving selectivity against
an off-target kinase, CK2. Potency in a cellular BCL6 assay was further
optimized to afford highly selective probe molecules. Only weak antiproliferative
effects were observed across a number of DLBCL lines and a multiple
myeloma cell line without a clear relationship to BCL6 potency. As
a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains
unproven