The first evidence of osimertinib resistance mediated by the epidermal growth factor receptor (EGFR) mutation C797S was reported three years ago. Since then, no major breakthroughs have been achieved to target the clinically relevant mutant variant that impedes covalent bond formation with irreversible EGFR inhibitors. Although several biochemically active compounds have been described, only a few inhibitors that potently act on the cellular level or have been introduced so far. Herein, we give an overview of current approaches in the field and highlight the challenges that need to be addressed in future research projects to overcome the C797S-mediated drug resistance.
We present inhibitors of drug resistant mutants of EGFR including T790M and C797S. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR to gain insight into their binding mode.
Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) and currently the gold-standard for the treatment of patients suffering from non-small cell lung cancer (NSCLC) harboring T790M-mutated epidermal growth factor receptor (EGFR). The outcome of the treatment, however, is limited by the emergence of the C797S resistance mutation. Allosteric inhibitors have a different mode of action and were developed to overcome this limitation. However, most of these innovative molecules are not effective as a single agent. Recently, mutated EGFR was successfully addressed with osimertinib combined with the allosteric inhibitor JBJ-04-125-02, but surprisingly, structural insights into their binding mode were lacking. Here, we present the first complex crystal structures of mutant EGFR in complex with third-generation inhibitors such as osimertinib and mavelertinib in the presence of simultaneously bound allosteric inhibitors. These structures highlight the possibility of further combinations targeting EGFR and lay the foundation for hybrid inhibitors as next-generation TKIs.
Surface-functional nanoparticles have been fabricated by utilizing bifunctional poly(2-oxazoline) macromonomers as surfactants in a microemulsion process.
Despite the clinical
efficacy of epidermal growth factor receptor
(EGFR) inhibitors, a subset of patients with non-small cell lung cancer
displays insertion mutations in exon20 in EGFR and Her2 with limited
treatment options. Here, we present the development and characterization
of the novel covalent inhibitors LDC8201 and LDC0496 based on a 1H-pyrrolo[2,3-b]pyridine scaffold. They
exhibited intense inhibitory potency toward EGFR and Her2 exon20 insertion
mutations as well as selectivity over wild type EGFR and within the
kinome. Complex crystal structures with the inhibitors and biochemical
and cellular on-target activity document their favorable binding characteristics.
Ultimately, we observed tumor shrinkage in mice engrafted with patient-derived
EGFR-H773_V774insNPH mutant cells during treatment with LDC8201. Together,
these results highlight the potential of covalent pyrrolopyridines
as inhibitors to target exon20 insertion mutations.
Mutated or amplified
Her2 serves as a driver of non-small cell
lung cancer or mediates resistance toward the inhibition of its family
member epidermal growth factor receptor with small-molecule inhibitors.
To date, small-molecule inhibitors targeting Her2 which can be used
in clinical routine are lacking, and therefore, the development of
novel inhibitors was undertaken. In this study, the well-established
pyrrolopyrimidine scaffold was modified with structural motifs identified
from a screening campaign with more than 1600 compounds, which were
applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA.
The resulting inhibitors were designed to covalently target a reactive
cysteine in the binding site of Her2 and were further optimized by
means of structure-based drug design utilizing a set of obtained complex
crystal structures. In addition, the analysis of binding kinetics
and absorption, distribution, metabolism, and excretion parameters
as well as mass spectrometry experiments and western blot analysis
substantiated our approach.
Drug resistance mutations emerging during the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors represent a major challenge in personalized cancer treatment and require constant development of new inhibitors. For the covalent irreversible EGFR inhibitor osimertinib, the predominant resistance mechanism is the acquired C797S mutation, which abolishes the covalent anchor point and thus results in a dramatic loss in potency. In this study, we present next-generation reversible EGFR inhibitors with the potential to overcome this EGFR-C797S resistance mutation. For this, we combined the reversible methylindole-aminopyrimidine scaffold known from osimertinib with the affinity driving isopropyl ester of mobocertinib. By occupying the hydrophobic back pocket, we were able to generate reversible inhibitors with subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S with cellular activity on EGFR-L858R/C797S dependent Ba/F3 cells. Additionally, we were able to resolve cocrystal structures of these reversible aminopyrimidines, which will guide further inhibitor design toward C797S-mutated EGFR.
Ten-eleven translocation dioxygenases (TETs) are the erasers of 5-methylcytosine (mC), the central epigenetic regulator of mammalian DNA. TETs convert mC to three oxidized derivatives with unique physicochemical properties and inherent...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.