2 research outputs found
Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors
Blockade of aberrant Wnt signaling
is an attractive therapeutic
approach in multiple cancers. We developed and performed a cellular
high-throughput screen for inhibitors of Wnt secretion and pathway
activation. A lead structure (GNF-1331) was identified from the screen.
Further studies identified the molecular target of GNF-1331 as Porcupine,
a membrane bound O-acyl transferase. Structure–activity relationship
studies led to the discovery of a novel series of potent and selective
Porcupine inhibitors. Compound <b>19</b>, GNF-6231, demonstrated
excellent pathway inhibition and induced robust antitumor efficacy
in a mouse MMTV-WNT1 xenograft tumor model
Discovery of (<i>R</i>,<i>E</i>)‑<i>N</i>‑(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)‑1<i>H</i>‑benzo[<i>d</i>]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers
Over the past decade, first and second
generation EGFR inhibitors have significantly improved outcomes for
lung cancer patients with activating mutations in EGFR. However, both
resistance through a secondary T790M mutation at the gatekeeper residue
and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately
limit the full potential of these therapies to control mutant EGFR-driven
tumors and new therapies are urgently needed. Herein, we describe
our approach toward the discovery of <b>47</b> (EGF816, nazartinib), a novel,
covalent mutant-selective EGFR inhibitor with equipotent activity
on both oncogenic and T790M-resistant EGFR mutations. Through molecular
docking studies we converted a mutant-selective high-throughput screening
hit (<b>7</b>) into a number of targeted covalent EGFR inhibitors
with equipotent activity across mutants EGFR and good WT-EGFR selectivity.
We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability
and efficacy that ultimately led to the selection of <b>47</b> as the clinical candidate