4 research outputs found
Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1 Inhibitors
We initiated our structure–activity
relationship (SAR) studies for selective ACC1 inhibitors from <b>1a</b> as a lead compound. SAR studies of bicyclic scaffolds revealed
many potent and selective ACC1 inhibitors represented by <b>1f</b>; however most of them had physicochemical issues, particularly low
aqueous solubility and potent CYP inhibition. To address these two
issues and improve the druglikeness of this chemical series, we converted
the bicyclic scaffold into a monocyclic framework. Ultimately, this
lead us to discover a novel monocyclic derivative <b>1q</b> as
a selective ACC1 inhibitor, which showed highly potent and selective
ACC1 inhibition as well as acceptable solubility and CYP inhibition
profiles. Since compound <b>1q</b> displayed favorable bioavailability
in mouse cassette dosing testing, we conducted in vivo PD studies
of this compound. Oral administration of <b>1q</b> significantly
reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors
at doses of more than 30 mg/kg. Accordingly, our novel series of selective
ACC1 inhibitors represents a set of useful orally available research
tools, as well as potential therapeutic agents for cancer and fatty
acid related diseases
Second-Generation AUTACs for Targeted Autophagic Degradation
Targeted protein degradation via the ubiquitin-proteasome
system
has emerged as one of the most promising drug discovery modalities.
Autophagy, another intracellular degradation system, can target a
wide range of nonproteinous substrates as well as proteins, but its
application to targeted degradation is still in its infancy. Our previous
work revealed a relationship between guanine modification of cysteine
residues on intracellular proteins and selective autophagy, resulting
in the first autophagy-based degraders, autophagy-targeted chimeras
(AUTACs). Based on the research background, all the reported AUTACs
compounds contain cysteine as a substructure. Here, we examine the
importance of this substructure by conducting SAR studies and report
significant improvements in the degrader’s activity by replacing
cysteine with other moieties. Several derivatives showed sub-μM
range degrading activity, demonstrating the increased practical value
of AUTACs
Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2
Brr2 is an RNA helicase
belonging to the Ski2-like subfamily and
an essential component of spliceosome. Brr2 catalyzes an ATP-dependent
unwinding of the U4/U6 RNA duplex, which is a critical step for spliceosomal
activation. An HTS campaign using an RNA-dependent ATPase assay and
initial SAR study identified two different Brr2 inhibitors, <b>3</b> and <b>12</b>. Cocrystal structures revealed <b>3</b> binds to an unexpected allosteric site between the C-terminal
and the N-terminal helicase cassettes, while <b>12</b> binds
an RNA-binding site inside the N-terminal cassette. Selectivity profiling
indicated the allosteric inhibitor <b>3</b> is more Brr2-selective
than the RNA site binder <b>12</b>. Chemical optimization of <b>3</b> using SBDD culminated in the discovery of the potent and
selective Brr2 inhibitor <b>9</b> with helicase inhibitory activity.
Our findings demonstrate an effective strategy to explore selective
inhibitors for helicases, and <b>9</b> could be a promising
starting point for exploring molecular probes to elucidate biological
functions and the therapeutic relevance of Brr2
Second-Generation AUTACs for Targeted Autophagic Degradation
Targeted protein degradation via the ubiquitin-proteasome
system
has emerged as one of the most promising drug discovery modalities.
Autophagy, another intracellular degradation system, can target a
wide range of nonproteinous substrates as well as proteins, but its
application to targeted degradation is still in its infancy. Our previous
work revealed a relationship between guanine modification of cysteine
residues on intracellular proteins and selective autophagy, resulting
in the first autophagy-based degraders, autophagy-targeted chimeras
(AUTACs). Based on the research background, all the reported AUTACs
compounds contain cysteine as a substructure. Here, we examine the
importance of this substructure by conducting SAR studies and report
significant improvements in the degrader’s activity by replacing
cysteine with other moieties. Several derivatives showed sub-μM
range degrading activity, demonstrating the increased practical value
of AUTACs