3 research outputs found
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
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
Targeting Gain of Function and Resistance Mutations in Abl and KIT by Hybrid Compound Design
Mutations
in the catalytic domain at the gatekeeper position represent the most
prominent drug-resistant variants of kinases and significantly impair
the efficacy of targeted cancer therapies. Understanding the mechanisms
of drug resistance at the molecular and atomic levels will aid in
the design and development of inhibitors that have the potential to
overcome these resistance mutations. Herein, by introducing adaptive
elements into the inhibitor core structure, we undertake the structure-based
development of type II hybrid inhibitors to overcome gatekeeper drug-resistant
mutations in cSrc-T338M, as well as clinically relevant tyrosine kinase
KIT-T670I and Abl-T315I variants, as essential targets in gastrointestinal
stromal tumors (GISTs) and chronic myelogenous leukemia (CML). Using
protein X-ray crystallography, we confirm the anticipated binding
mode in cSrc, which proved to be essential for overcoming the respective
resistances. More importantly, the novel compounds effectively inhibit
clinically relevant gatekeeper mutants of KIT and Abl in biochemical
and cellular studies