7 research outputs found
Discovery of Potent and Selective Leads against <i>Toxoplasma gondii</i> Dihydrofolate Reductase via Structure-Based Design
Current
treatment of toxoplasmosis targets the parasite’s folate metabolism
through inhibition of dihydrofolate reductase (DHFR). The most widely
used DHFR antagonist, pyrimethamine, was introduced over 60 years
ago and is associated with toxicity that can be largely attributed
to a similar affinity for parasite and human DHFR. Computational analysis
of biochemical differences between <i>Toxoplasma gondii</i> and human DHFR enabled the design of inhibitors with both improved
potency and selectivity. The approach described herein yielded TRC-19,
a promising lead with an IC<sub>50</sub> of 9 nM and 89-fold selectivity
in favor of <i>Toxoplasma gondii</i> DHFR, as well as crystallographic
data to substantiate <i>in silico</i> methodology. Overall,
50% of synthesized <i>in silico</i> designs met hit threshold
criteria of IC<sub>50</sub> < 10 μM and >2-fold selectivity
favoring <i>Toxoplasma gondii</i>, further demonstrating
the efficiency of our structure-based drug design approach
A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors
The
epigenetic regulator CBP/P300 presents a novel therapeutic
target for oncology. Previously, we disclosed the development of potent
and selective CBP bromodomain inhibitors by first identifying pharmacophores
that bind the KAc region and then building into the LPF shelf. Herein,
we report the “hybridization” of a variety of KAc-binding
fragments with a tetrahydroquinoline scaffold that makes optimal interactions
with the LPF shelf, imparting enhanced potency and selectivity to
the hybridized ligand. To demonstrate the utility of our hybridization
approach, two analogues containing unique Asn binders and the optimized
tetrahydroquinoline moiety were rapidly optimized to yield single-digit
nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1)
and the broader bromodomain family
Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice
A series
of trisubstituted hydroxylactams was identified as potent
enzymatic and cellular inhibitors of human lactate dehydrogenase A.
Utilizing structure-based design and physical property optimization,
multiple inhibitors were discovered with <10 μM lactate IC<sub>50</sub> in a MiaPaca2 cell line. Optimization of the series led
to <b>29</b>, a potent cell active molecule (MiaPaca2 IC<sub>50</sub> = 0.67 μM) that also possessed good exposure when
dosed orally to mice
Identification and in Vivo Evaluation of Liver X Receptor β‑Selective Agonists for the Potential Treatment of Alzheimer’s Disease
Herein, we describe the development
of a functionally selective
liver X receptor β (LXRβ) agonist series optimized for
Emax selectivity, solubility, and physical properties to allow efficacy
and safety studies in vivo. Compound <b>9</b> showed central
pharmacodynamic effects in rodent models, evidenced by statistically
significant increases in apolipoprotein E (apoE) and ATP-binding cassette
transporter levels in the brain, along with a greatly improved peripheral
lipid safety profile when compared to those of full dual agonists.
These findings were replicated by subchronic dosing studies in non-human
primates, where cerebrospinal fluid levels of apoE and amyloid-β
peptides were increased concomitantly with an improved peripheral
lipid profile relative to that of nonselective compounds. These results
suggest that optimization of LXR agonists for Emax selectivity may
have the potential to circumvent the adverse lipid-related effects
of hepatic LXR activity
GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)
Inhibition of the bromodomain of
the transcriptional regulator
CBP/P300 is an especially interesting new therapeutic approach in
oncology. We recently disclosed in vivo chemical tool <b>1</b> (GNE-272) for the bromodomain of CBP that was moderately potent
and selective over BRD4(1). In pursuit of a more potent and selective
CBP inhibitor, we used structure-based design. Constraining the aniline
of <b>1</b> into a tetrahydroquinoline motif maintained potency
and increased selectivity 2-fold. Structure–activity relationship
studies coupled with further structure-based design targeting the
LPF shelf, BC loop, and KAc regions allowed us to significantly increase
potency and selectivity, resulting in the identification of non-CNS
penetrant <b>19</b> (GNE-781, TR-FRET IC<sub>50</sub> = 0.94
nM, BRET IC<sub>50</sub> = 6.2 nM; BRD4(1) IC<sub>50</sub> = 5100
nΜ) that maintained good in vivo PK properties in multiple species.
Compound <b>19</b> displays antitumor activity in an AML tumor
model and was also shown to decrease Foxp3 transcript levels in a
dose dependent manner
Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300
The single bromodomain of the closely
related transcriptional regulators
CBP/EP300 is a target of much recent interest in cancer and immune
system regulation. A co-crystal structure of a ligand-efficient screening
hit and the CBP bromodomain guided initial design targeting the LPF
shelf, ZA loop, and acetylated lysine binding regions. Structure–activity
relationship studies allowed us to identify a more potent analogue.
Optimization of permeability and microsomal stability and subsequent
improvement of mouse hepatocyte stability afforded <b>59</b> (GNE-272, TR-FRET IC<sub>50</sub> = 0.02 μM, BRET IC<sub>50</sub> = 0.41 μM, BRD4(1) IC<sub>50</sub> = 13 μM) that retained
the best balance of cell potency, selectivity, and in vivo PK. Compound <b>59</b> showed a marked antiproliferative effect in hematologic
cancer cell lines and modulates <i>MYC</i> expression in
vivo that corresponds with antitumor activity in an AML tumor model
Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)
CBP and EP300 are highly homologous,
bromodomain-containing transcription
coactivators involved in numerous cellular pathways relevant to oncology.
As part of our effort to explore the potential therapeutic implications
of selectively targeting bromodomains, we set out to identify a CBP/EP300
bromodomain inhibitor that was potent both <i>in vitro</i> and in cellular target engagement assays and was selective over
the other members of the bromodomain family. Reported here is a series
of cell-potent and selective probes of the CBP/EP300 bromodomains,
derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2<i>H</i>-benzo[<i>b</i>][1,4]diazepin-2-one