Dataset Information

Discovery of Nanomolar DCAF1 Small Molecule Ligands.

ABSTRACT: DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4^DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR K_D of 11 μM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR K_D of 38 nM and cellular target engagement with EC₅₀ of 10 μM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.

SUBMITTER: Li ASM

PROVIDER: S-EPMC10108359 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Discovery of Nanomolar DCAF1 Small Molecule Ligands.

Li Alice Shi Ming ASM Kimani Serah S Wilson Brian B Noureldin Mahmoud M González-Álvarez Héctor H Mamai Ahmed A Hoffer Laurent L Guilinger John P JP Zhang Ying Y von Rechenberg Moritz M Disch Jeremy S JS Mulhern Christopher J CJ Slakman Belinda L BL Cuozzo John W JW Dong Aiping A Poda Gennady G Mohammed Mohammed M Saraon Punit P Mittal Manish M Modh Pratik P Rathod Vaibhavi V Patel Bhashant B Ackloo Suzanne S Santhakumar Vijayaratnam V Szewczyk Magdalena M MM Barsyte-Lovejoy Dalia D Arrowsmith Cheryl H CH Marcellus Richard R Guié Marie-Aude MA Keefe Anthony D AD Brown Peter J PJ Halabelian Levon L Al-Awar Rima R Vedadi Masoud M

Journal of medicinal chemistry 20230322 7

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4<sup>DCAF1</sup> and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the d ...[more]

PMID: 36948210

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Project description:The trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine scaffold is a known pharmacophore for mu opioid (MOP), kappa opioid (KOP), and delta opioid (DOP) receptor antagonists; however, it has not been explored in nociceptin opioid (NOP/ORL-1) receptor ligands. We recently found that the selective KOP antagonist JDTic, (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide, containing this opioid antagonist pharmacophore, has significant binding affinity at the NOP receptor (Ki 16.67 ± 0.76 nM), with no intrinsic activity in the [(35)S]GTPγS functional assay. Since this is the first ligand containing the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist pharmacophore to have affinity for the NOP receptor, we explored the structural determinants of its NOP binding affinity. When rational chemical modifications of JDTic were carried out, based on our previously established NOP pharmacophoric structure-activity relationship (SAR) model, most modifications led to a significant decrease in NOP and opioid binding affinity compared to JDTic. Interestingly, however, removal of the 3,4-dimethyl groups of the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine antagonist scaffold of JDTic increased the binding affinity at NOP by 10-fold (Ki 1.75 ± 0.74 nM) while maintaining comparable affinity for KOP, MOP, and DOP receptors (Ki 1.14 ± 0.63, 1.67 ± 0.6, and 19.6 ± 1.3 nM, respectively). In vitro functional efficacy studies using the [(35)S]GTPγS assay showed that this compound AT-076 functions as an antagonist at all four opioid receptors. Detailed characterization of the antagonist activity of AT-076 shows that it has a noncompetitive antagonist profile at the NOP and KOP receptors (insurmountable antagonism), but is a potent competitive antagonist at the MOP and DOP receptors, with Ke values 3-6-fold more potent than those of JDTic. AT-076 is the first opioid pan antagonist with high affinity at all four opioid receptor subtypes. Our SAR studies show that the 3,4-dimethyl groups of the well-known trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist scaffold may be removed without significant loss in binding affinity or antagonist potency to obtain an opioid pan antagonist such as AT-076.

Dataset Information

Discovery of Nanomolar DCAF1 Small Molecule Ligands.

Publications

Discovery of Nanomolar DCAF1 Small Molecule Ligands.

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