5 research outputs found
Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)
In the search of PI3K p110α
wild type and H1047R mutant selective small molecule leads, an encoded
library technology (ELT) campaign against the desired target proteins
was performed which led to the discovery of a selective chemotype
for PI3K isoforms from a three-cycle DNA encoded library. An X-ray
crystal structure of a representative inhibitor from this chemotype
demonstrated a unique binding mode in the p110α protein
Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis
Potent inhibitors of RIP1 kinase
from three distinct series, 1-aminoisoquinolines,
pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type
II class recognizing a DLG-out inactive conformation, were identified
from screening of our in-house kinase focused sets. An exemplar from
the furo[2,3-d]pyrimidine series showed a dose proportional response
in protection from hypothermia in a mouse model of TNFα induced
lethal shock
DNA-Encoded Library Screening Identifies Benzo[<i>b</i>][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors
The
recent discovery of the role of receptor interacting protein
1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation
has led to its emergence as a highly promising target for the treatment
of multiple inflammatory diseases. We screened RIP1 against GSK’s
DNA-encoded small-molecule libraries and identified a novel highly
potent benzoxazepinone inhibitor series. We demonstrate that this
template possesses complete monokinase selectivity for RIP1 plus unique
species selectivity for primate versus nonprimate RIP1. We elucidate
the conformation of RIP1 bound to this benzoxazepinone inhibitor driving
its high kinase selectivity and design specific mutations in murine
RIP1 to restore potency to levels similar to primate RIP1. This series
differentiates itself from known RIP1 inhibitors in combining high
potency and kinase selectivity with good pharmacokinetic profiles
in rodents. The favorable developability profile of this benzoxazepinone
template, as exemplified by compound <b>14</b> (GSK’481),
makes it an excellent starting point for further optimization into
a RIP1 clinical candidate
DNA-Encoded Library Screening Identifies Benzo[<i>b</i>][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors
The
recent discovery of the role of receptor interacting protein
1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation
has led to its emergence as a highly promising target for the treatment
of multiple inflammatory diseases. We screened RIP1 against GSK’s
DNA-encoded small-molecule libraries and identified a novel highly
potent benzoxazepinone inhibitor series. We demonstrate that this
template possesses complete monokinase selectivity for RIP1 plus unique
species selectivity for primate versus nonprimate RIP1. We elucidate
the conformation of RIP1 bound to this benzoxazepinone inhibitor driving
its high kinase selectivity and design specific mutations in murine
RIP1 to restore potency to levels similar to primate RIP1. This series
differentiates itself from known RIP1 inhibitors in combining high
potency and kinase selectivity with good pharmacokinetic profiles
in rodents. The favorable developability profile of this benzoxazepinone
template, as exemplified by compound <b>14</b> (GSK’481),
makes it an excellent starting point for further optimization into
a RIP1 clinical candidate
Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases
RIP1
regulates necroptosis and inflammation and may play an important role
in contributing to a variety of human pathologies, including immune-mediated
inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that
are suitable for advancement into the clinic have yet to be described.
Herein, we report our lead optimization of a benzoxazepinone hit from
a DNA-encoded library and the discovery and profile of clinical candidate
GSK2982772 (compound <b>5</b>), currently in phase 2a clinical
studies for psoriasis, rheumatoid arthritis, and ulcerative colitis.
Compound <b>5</b> potently binds to RIP1 with exquisite kinase
specificity and has excellent activity in blocking many TNF-dependent
cellular responses. Highlighting its potential as a novel anti-inflammatory
agent, the inhibitor was also able to reduce spontaneous production
of cytokines from human ulcerative colitis explants. The highly favorable
physicochemical and ADMET properties of <b>5</b>, combined with
high potency, led to a predicted low oral dose in humans