4 research outputs found
Novel and Versatile Synthesis of Disubstituted 1,2-Dihydro-1,2,4-triazol-3-ones
A novel method for the synthesis of a wide range of 1,5-disubstituted
1,2-dihydro-1,2,4-triazol-3-ones is described. The key step involves
a reaction between a dilithiated BOC-hydrazine and a <i>N</i>-alkoxycarbonylcarboximidothioate. A broad range of aryl and alkyl
functional groups are tolerated, providing a versatile route for the
synthesis of triazolones
Novel and Versatile Synthesis of Disubstituted 1,2-Dihydro-1,2,4-triazol-3-ones
A novel method for the synthesis of a wide range of 1,5-disubstituted
1,2-dihydro-1,2,4-triazol-3-ones is described. The key step involves
a reaction between a dilithiated BOC-hydrazine and a <i>N</i>-alkoxycarbonylcarboximidothioate. A broad range of aryl and alkyl
functional groups are tolerated, providing a versatile route for the
synthesis of triazolones
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 a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor
Epidermal growth factor receptor
(EGFR) inhibitors have been used clinically in the treatment of non-small-cell
lung cancer (NSCLC) patients harboring sensitizing (or activating)
mutations for a number of years. Despite encouraging clinical efficacy
with these agents, in many patients resistance develops leading to
disease progression. In most cases, this resistance is in the form
of the T790M mutation. In addition, EGFR wild type receptor inhibition
inherent with these agents can lead to dose limiting toxicities of
rash and diarrhea. We describe herein the evolution of an early, mutant
selective lead to the clinical candidate AZD9291, an irreversible
inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations
with selectivity over the wild type form of the receptor. Following
observations of significant tumor inhibition in preclinical models,
the clinical candidate was administered clinically to patients with
T790M positive EGFR-TKI resistant NSCLC and early efficacy has been
observed, accompanied by an encouraging safety profile