13 research outputs found
Trisubstituted Imidazoles with a Rigidized Hinge Binding Motif Act As Single Digit nM Inhibitors of Clinically Relevant EGFR L858R/T790M and L858R/T790M/C797S Mutants: An Example of Target Hopping
The
high genomic instability of non-small cell lung cancer tumors
leads to the rapid development of resistance against promising EGFR
tyrosine kinase inhibitors (TKIs). A recently detected triple mutation
compromises the activity of the gold standard third-generation EGFR
inhibitors. We have prepared a set of trisubstituted imidazoles with
a rigidized 7-azaindole hinge binding motif as a new structural class
of EGFR inhibitors by a target hopping approach from p38α MAPK
inhibitor templates. On the basis of an iterative approach of docking,
compound preparation, biological testing, and SAR interpretation,
robust and flexible synthetic routes were established. As a result,
we report two reversible inhibitors <b>11d</b> and <b>11e</b> of the clinically challenging triple mutant L858R/T790M/C797S with
IC<sub>50</sub> values in the low nanomolar range. Furthermore, we
developed a kinome selective irreversible inhibitor <b>45a</b> with an IC<sub>50</sub> value of 1 nM against the EGFR L858R/T790M
double mutant. Target binding kinetics and metabolic stability data
are included. These potent mutant EGFR inhibitors may serve as a basis
for the development of structurally novel EGFR probes, tools, or candidates
Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site
Inhibition
of the epidermal growth factor receptor represents one
of the most promising strategies in the treatment of lung cancer.
Acquired resistance compromises the clinical efficacy of EGFR inhibitors
during long-term treatment. The recently discovered EGFR-C797S mutation
causes resistance against third-generation EGFR inhibitors. Here we
present a rational approach based on extending the inhibition profile
of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used
a privileged scaffold with proven cellular potency as well as in vivo
efficacy and low toxicity. Guided by molecular modeling, we synthesized
and studied the structure–activity relationship of 40 compounds
against clinically relevant EGFR mutants. We successfully improved
the cellular EGFR inhibition down to the low nanomolar range with
covalently binding inhibitors against a gefitinib resistant T790M
mutant cell line. We identified additional noncovalent interactions,
which allowed us to develop metabolically stable inhibitors with high
activities against the osimertinib resistant L858R/T790M/C797S mutant
Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site
Inhibition
of the epidermal growth factor receptor represents one
of the most promising strategies in the treatment of lung cancer.
Acquired resistance compromises the clinical efficacy of EGFR inhibitors
during long-term treatment. The recently discovered EGFR-C797S mutation
causes resistance against third-generation EGFR inhibitors. Here we
present a rational approach based on extending the inhibition profile
of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used
a privileged scaffold with proven cellular potency as well as in vivo
efficacy and low toxicity. Guided by molecular modeling, we synthesized
and studied the structure–activity relationship of 40 compounds
against clinically relevant EGFR mutants. We successfully improved
the cellular EGFR inhibition down to the low nanomolar range with
covalently binding inhibitors against a gefitinib resistant T790M
mutant cell line. We identified additional noncovalent interactions,
which allowed us to develop metabolically stable inhibitors with high
activities against the osimertinib resistant L858R/T790M/C797S mutant