4 research outputs found

    Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1 Inhibitors

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    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

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    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

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    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

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    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
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