9 research outputs found
Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase
5′-Adenosine
monophosphate-activated protein kinase (AMPK)
is a key regulator of mammalian energy homeostasis and has been implicated
in mediating many of the beneficial effects of exercise and weight
loss including lipid and glucose trafficking. As such, the enzyme
has long been of interest as a target for the treatment of Type 2
Diabetes Mellitus. We describe the optimization of β1-selective,
liver-targeted AMPK activators and their evolution into systemic pan-activators
capable of acutely lowering glucose in mouse models. Identifying surrogates
for the key acid moiety in early generation compounds proved essential
in improving β2-activation and in balancing improvements in
plasma unbound fraction while avoiding liver sequestration
Hit-to-Lead Optimization and Discovery of 5‑((5-([1,1′-Biphenyl]-4-yl)-6-chloro‑1<i>H</i>‑benzo[<i>d</i>]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase
AMP-activated protein kinase (AMPK)
plays an essential role as
a cellular energy sensor and master regulator of metabolism in eukaryotes.
Dysregulated lipid and carbohydrate metabolism resulting from insulin
resistance leads to hyperglycemia, the hallmark of type 2 diabetes
mellitus (T2DM). While pharmacological activation of AMPK is anticipated
to improve these parameters, the discovery of selective, direct activators
has proven challenging. We now describe a hit-to-lead effort resulting
in the discovery of a potent and selective class of benzimidazole-based
direct AMPK activators, exemplified by 5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1<i>H</i>-benzo[<i>d</i>]imidazol-2-yl)oxy)-2-methylbenzoic
acid, <b>42</b> (MK-3903). Compound <b>42</b> exhibited
robust target engagement in mouse liver following oral dosing, leading
to improved lipid metabolism and insulin sensitization in mice
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
GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)
The
biological function of bromodomains, epigenetic readers of
acetylated lysine residues, remains largely unknown. Herein we report
our efforts to discover a potent and selective inhibitor of the bromodomain
of cat eye syndrome chromosome region candidate 2 (CECR2). Screening
of our internal medicinal chemistry collection led to the identification
of a pyrrolopyridone chemical lead, and subsequent structure-based
drug design led to a potent and selective CECR2 bromodomain inhibitor
(GNE-886) suitable for use as an in vitro tool compound
GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)
The
biological function of bromodomains, epigenetic readers of
acetylated lysine residues, remains largely unknown. Herein we report
our efforts to discover a potent and selective inhibitor of the bromodomain
of cat eye syndrome chromosome region candidate 2 (CECR2). Screening
of our internal medicinal chemistry collection led to the identification
of a pyrrolopyridone chemical lead, and subsequent structure-based
drug design led to a potent and selective CECR2 bromodomain inhibitor
(GNE-886) suitable for use as an in vitro tool compound
Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains
The
biological role played by non-BET bromodomains remains poorly understood,
and it is therefore imperative to identify potent and highly selective
inhibitors to effectively explore the biology of individual bromodomain
proteins. A ligand-efficient nonselective bromodomain inhibitor was
identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic
substituents replacing the <i>N</i>-methyl group were designed
directing toward the conserved bromodomain water pocket, and two distinct
binding conformations were then observed. The substituents either
directly displaced and rearranged the conserved solvent network, as
in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent
to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct
substituents for individual bromodomains provided selectivity handles
useful for future lead optimization efforts for selective BRD9, CECR2,
and TAF1(2) inhibitors
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