5 research outputs found
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
Indazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor
The specific targeting of oncogenic
mutant epidermal growth factor
receptor (EGFR) is a breakthrough in targeted cancer therapy and marks
a drastic change in the treatment of non-small cell lung cancer (NSCLC).
The recurrent emergence of resistance to these targeted drugs requires
the development of novel chemical entities that efficiently inhibit
drug-resistant EGFR. Herein, we report the optimization process for
a hit compound that has emerged from a phenotypic screen resulting
in indazole-based compounds. These inhibitors are conformationally
less flexible, target gatekeeper mutated drug-resistant EGFR-L858R/T790M,
and covalently alkylate Cys797. Western blot analysis, as well as
characterization of the binding kinetics and kinase selectivity profiling,
substantiates our approach of targeting drug-resistant EGFR-L858R/T790M
with inhibitors incorporating the indazole as hinge binder
Inhibitors to Overcome Secondary Mutations in the Stem Cell Factor Receptor KIT
In modern cancer therapy, the use
of small organic molecules against
receptor tyrosine kinases (RTKs) has been shown to be a valuable strategy.
The association of cancer cells with dysregulated signaling pathways
linked to RTKs represents a key element in targeted cancer therapies.
The tyrosine kinase mast/stem cell growth factor receptor KIT is an
example of a clinically relevant RTK. KIT is targeted for cancer therapy
in gastrointestinal stromal tumors (GISTs) and chronic myelogenous
leukemia (CML). However, acquired resistance mutations within the
catalytic domain decrease the efficacy of this strategy and are the
most common cause of failed therapy. Here, we present the structure-based
design and synthesis of novel type II kinase inhibitors to overcome
these mutations in KIT. Biochemical and cellular studies revealed
promising molecules for the inhibition of mutated KIT
Structure-Guided Development of Covalent and Mutant-Selective Pyrazolopyrimidines to Target T790M Drug Resistance in Epidermal Growth Factor Receptor
Reversible
epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial
clinical response in non-small cell lung cancer patients who harbor
activating mutations in EGFR. However, resistance mutations, particularly
the gatekeeper mutation T790M, limit this efficacy. Here, we describe
a structure-guided development of a series of covalent and mutant-selective
EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based
core differs structurally from that of aminopyrimidine-based third-generation
EGFR inhibitors and therefore constitutes a new set of inhibitors
that target this mechanism of drug resistance. These inhibitors exhibited
strong inhibitory effects toward EGFR kinase activity and excellent
inhibition of cell growth in the drug-resistant cell line H1975, without
significantly affecting EGFR wild-type cell lines. Additionally, we
present the in vitro ADME/DMPK parameters for a subset of the inhibitors
as well as in vivo pharmacokinetics in mice for a candidate with promising
activity profile