10 research outputs found
Protein-Ligand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase
ProteināLigand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase
The design of compounds that selectively inhibit a single
kinase
is a significant challenge, particularly for compounds that bind to
the ATP site. We describe here how proteināligand crystal structure
information was able both to rationalize observed selectivity and
to guide the design of more selective compounds. Inhibition data from
enzyme and cellular screens and the crystal structures of a range
of ligands tested during the process of identifying selective inhibitors
of FGFR provide a step-by-step illustration of the process. Steric
effects were exploited by increasing the size of ligands in specific
regions in such a way as to be tolerated in the primary target and
not in other related kinases. Kinases are an excellent target class
to exploit such approaches because of the conserved fold and small
side chain mobility of the active form
Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR)
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer
First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle. SIGNIFICANCE: We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented. (C) 2014 AACR.
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
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
Computer clinical decision support that automates personalized clinical care:a challenging but needed healthcare delivery strategy
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