3 research outputs found
Discovery of 4‑Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys
Inappropriately high levels of aldosterone
are associated with
many serious medical conditions, including renal and cardiac failure.
A focused screen hit has been optimized into a potent and selective
aldosterone synthase (CYP11B2) inhibitor with in vitro activity against
rat, mouse, human, and cynomolgus monkey enzymes, showing a selectivity
factor of 160 against cytochrome CYP11B1 in the last species. The
novel tetrahydroisoquinoline compound (+)-(<i>R</i>)-<b>6</b> selectively reduced aldosterone plasma levels in vivo in
a dose-dependent manner in db/db mice and cynomolgus monkeys. The
selectivity against CYP11B1 as predicted by cellular inhibition data
and free plasma fraction translated well to Synacthen challenged cynomolgus
monkeys up to a dose of 0.1 mg kg<sup>–1</sup>. This compound,
displaying good in vivo potency and selectivity in mice and monkeys,
is ideally suited to perform mechanistic studies in relevant rodent
models and to provide the information necessary for translation to
non-human primates and ultimately to man
Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib
Addressing resistance to third-generation EGFR TKIs such
as osimertinib
via the EGFRC797S mutation remains a highly unmet need
in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present
the discovery of the allosteric EGFR inhibitor 57, a
novel fourth-generation inhibitor to overcome EGFRC797S-mediated resistance in patients harboring the activating EGFRL858R mutation. 57 exhibits an improved potency
compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates
robust tumor regression in a mutant EGFRL858R/C797S tumor
model. Additionally, 57 is active in an H1975 EGFRL858R/T790M NSCLC xenograft model and shows superior efficacy
in combination with osimertinib compared to the single agents. Our
data highlight the potential of 57 as a single agent
against EGFRL858R/C797S and EGFRL858R/T790M/C797S and as combination therapy for EGFRL858R- and EGFRL858R/T790M-driven NSCLC
Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib
Addressing resistance to third-generation EGFR TKIs such
as osimertinib
via the EGFRC797S mutation remains a highly unmet need
in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present
the discovery of the allosteric EGFR inhibitor 57, a
novel fourth-generation inhibitor to overcome EGFRC797S-mediated resistance in patients harboring the activating EGFRL858R mutation. 57 exhibits an improved potency
compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates
robust tumor regression in a mutant EGFRL858R/C797S tumor
model. Additionally, 57 is active in an H1975 EGFRL858R/T790M NSCLC xenograft model and shows superior efficacy
in combination with osimertinib compared to the single agents. Our
data highlight the potential of 57 as a single agent
against EGFRL858R/C797S and EGFRL858R/T790M/C797S and as combination therapy for EGFRL858R- and EGFRL858R/T790M-driven NSCLC