2 research outputs found
Discovery of Potent 2‑Aryl-6,7-dihydro‑5<i>H</i>‑pyrrolo[1,2‑<i>a</i>]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design
WDR5
is a chromatin-regulatory scaffold protein overexpressed in
various cancers and a potential epigenetic drug target for the treatment
of mixed-lineage leukemia. Here, we describe the discovery of potent
and selective WDR5-WIN-site inhibitors using fragment-based methods
and structure-based design. NMR-based screening of a large fragment
library identified several chemically distinct hit series that bind
to the WIN site within WDR5. Members of a 6,7-dihydro-5<i>H</i>-pyrroloÂ[1,2-<i>a</i>]Âimidazole fragment class were expanded
using a structure-based design approach to arrive at lead compounds
with dissociation constants <10 nM and micromolar cellular activity
against an AML-leukemia cell line. These compounds represent starting
points for the discovery of clinically useful WDR5 inhibitors for
the treatment of cancer
Discovery of Potent 2‑Aryl-6,7-dihydro‑5<i>H</i>‑pyrrolo[1,2‑<i>a</i>]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design
WDR5
is a chromatin-regulatory scaffold protein overexpressed in
various cancers and a potential epigenetic drug target for the treatment
of mixed-lineage leukemia. Here, we describe the discovery of potent
and selective WDR5-WIN-site inhibitors using fragment-based methods
and structure-based design. NMR-based screening of a large fragment
library identified several chemically distinct hit series that bind
to the WIN site within WDR5. Members of a 6,7-dihydro-5<i>H</i>-pyrroloÂ[1,2-<i>a</i>]Âimidazole fragment class were expanded
using a structure-based design approach to arrive at lead compounds
with dissociation constants <10 nM and micromolar cellular activity
against an AML-leukemia cell line. These compounds represent starting
points for the discovery of clinically useful WDR5 inhibitors for
the treatment of cancer