4 research outputs found
Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors
The
chromatin-associated protein WDR5 (WD repeat domain 5) is an
essential cofactor for MYC and a conserved regulator of ribosome protein
gene transcription. It is also a high-profile target for anti-cancer
drug discovery, with proposed utility against both solid and hematological
malignancies. We have previously discovered potent dihydroisoquinolinone-based
WDR5 WIN-site inhibitors with demonstrated efficacy and safety in
animal models. In this study, we sought to optimize the bicyclic core
to discover a novel series of WDR5 WIN-site inhibitors with improved
potency and physicochemical properties. We identified the 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one core as an alternative
scaffold for potent WDR5 inhibitors. Additionally, we used X-ray structural
analysis to design partially saturated bicyclic P7 units.
These benzoxazepinone-based inhibitors exhibited increased cellular
potency and selectivity and favorable physicochemical properties
compared to our best-in-class dihydroisoquinolinone-based counterparts.
This study opens avenues to discover more advanced WDR5 WIN-site inhibitors
and supports their development as novel anti-cancer therapeutics
Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors
The
chromatin-associated protein WDR5 (WD repeat domain 5) is an
essential cofactor for MYC and a conserved regulator of ribosome protein
gene transcription. It is also a high-profile target for anti-cancer
drug discovery, with proposed utility against both solid and hematological
malignancies. We have previously discovered potent dihydroisoquinolinone-based
WDR5 WIN-site inhibitors with demonstrated efficacy and safety in
animal models. In this study, we sought to optimize the bicyclic core
to discover a novel series of WDR5 WIN-site inhibitors with improved
potency and physicochemical properties. We identified the 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one core as an alternative
scaffold for potent WDR5 inhibitors. Additionally, we used X-ray structural
analysis to design partially saturated bicyclic P7 units.
These benzoxazepinone-based inhibitors exhibited increased cellular
potency and selectivity and favorable physicochemical properties
compared to our best-in-class dihydroisoquinolinone-based counterparts.
This study opens avenues to discover more advanced WDR5 WIN-site inhibitors
and supports their development as novel anti-cancer therapeutics
Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)
We report the discovery and medicinal
chemistry optimization of
a novel series of pyrazole-based inhibitors of human lactate dehydrogenase
(LDH). Utilization of a quantitative high-throughput screening paradigm
facilitated hit identification, while structure-based design and multiparameter
optimization enabled the development of compounds with potent enzymatic
and cell-based inhibition of LDH enzymatic activity. Lead compounds
such as <b>63</b> exhibit low nM inhibition of both LDHA and
LDHB, submicromolar inhibition of lactate production, and inhibition
of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells.
Moreover, robust target engagement of LDHA by lead compounds was demonstrated
using the cellular thermal shift assay (CETSA), and drug–target
residence time was determined via SPR. Analysis of these data suggests
that drug–target residence time (off-rate) may be an important
attribute to consider for obtaining potent cell-based inhibition of
this cancer metabolism target
Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)
We report the discovery and medicinal
chemistry optimization of
a novel series of pyrazole-based inhibitors of human lactate dehydrogenase
(LDH). Utilization of a quantitative high-throughput screening paradigm
facilitated hit identification, while structure-based design and multiparameter
optimization enabled the development of compounds with potent enzymatic
and cell-based inhibition of LDH enzymatic activity. Lead compounds
such as <b>63</b> exhibit low nM inhibition of both LDHA and
LDHB, submicromolar inhibition of lactate production, and inhibition
of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells.
Moreover, robust target engagement of LDHA by lead compounds was demonstrated
using the cellular thermal shift assay (CETSA), and drug–target
residence time was determined via SPR. Analysis of these data suggests
that drug–target residence time (off-rate) may be an important
attribute to consider for obtaining potent cell-based inhibition of
this cancer metabolism target