3 research outputs found
Design and Application of a DNA-Encoded Macrocyclic Peptide Library
A DNA-encoded
macrocyclic peptide library was designed and synthesized
with 2.4 × 10<sup>12</sup> members composed of 4–20 natural
and non-natural amino acids. Affinity-based selection was performed
against two therapeutic targets, VHL and RSV N protein. On the basis
of selection data, some peptides were selected for resynthesis without
a DNA tag, and their activity was confirmed
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