Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5–MYC Protein–Protein Interaction

Macdonald, Jonathan D.; Simon, Selena Chacón; Han, Chungyong; Wang, Feng; Shaw, J. Grace; Howes, Jennifer E.; Sai, Jiqing; Yuh, Joannes P.; Camper, DeMarco V.; Alicie, Bethany M.; Alvarado, Joseph; Nikhar, Sameer; Payne, William G.; Aho, Erin R.; Bauer, Joshua A.; Zhao, Bin; Phan, Jason; Thomas, Lance R.; Rossanese, Olivia W.; Tansey, William P.; Waterson, Alex G.; Stauffer, Shaun R.; Fesik, Stephen W.

doi:10.1021/acs.jmedchem.9b01411

Cited by 47 publications

(82 citation statements)

References 54 publications

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“…From Figure 3 , we can realize that the arginine residue stretches into the deep pocket of WIN site, which formed extensive hydrogen bonding interactions with nearby residues and water molecules. Comparing to WDR5 bound with a peptide segment from MLL2 (PDB ID: 3UVK) [ 25 ], it was found that the arginine residue from MLL2 is located at the exact same position as in our solved structure, further indicating it is important for the binding interactions ( Supplementary Information see Figure S4 ). Besides, the positive-charge nature of guanidyl group sandwiched between two aromatic residues Phe133 and Phe263, forming the typical cation-Pi interactions.…”

Section: Resultsmentioning

confidence: 78%

Phage-Display Based Discovery and Characterization of Peptide Ligands against WDR5

Cao

Fan

et al. 2021

Molecules

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WD40 is a ubiquitous domain presented in at least 361 human proteins and acts as scaffold to form protein complexes. Among them, WDR5 protein is an important mediator in several protein complexes to exert its functions in histone modification and chromatin remodeling. Therefore, it was considered as a promising epigenetic target involving in anti-cancer drug development. In view of the protein–protein interaction nature of WDR5, we initialized a campaign to discover new peptide-mimic inhibitors of WDR5. In current study, we utilized the phage display technique and screened with a disulfide-based cyclic peptide phage library. Five rounds of biopanning were performed and isolated clones were sequenced. By analyzing the sequences, total five peptides were synthesized for binding assay. The four peptides are shown to have the moderate binding affinity. Finally, the detailed binding interactions were revealed by solving a WDR5-peptide cocrystal structure.

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Section: Resultsmentioning

confidence: 78%

Phage-Display Based Discovery and Characterization of Peptide Ligands against WDR5

Cao

Fan

et al. 2021

Molecules

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“…So manual test is feasible, but for a limited number of samples. We took ten articles [28][29][30][31][32][33][34][35][36][37] to test our method on the real data. Structures that represent reaction mechanisms were excluded, so we regarded only molecules and Markush templates.…”

Section: Validation On Real Datamentioning

confidence: 99%

Image2SMILES: Transformer-based Molecular Optical Recognition Engine

Khokhlov¹,

Krasnov²,

Fedorov³

et al. 2021

Preprint

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The rise of deep learning in various scientific and technology areas promotes the development of AI-based tools for information retrieval. Optical recognition of organic structures is a key part of the automated extraction of chemical information. However, this is a challenging task because there is a large variety of representation styles. In this research, we present a Transformer-based artificial neural network to convert images of organic structures to molecular structures. To train the model, we created a comprehensive data generator that stochastically simulates various drawing styles, functional groups, functional group placeholders (R-groups), and visual contamination. We demonstrate that the Transformer-based architecture can gather chemical insights from our generator with almost absolute confidence. That means that, with Transformer, one can fully concentrate on data simulation to build a good recognition model. A web demo of our optical recognition engine is available online at <i>Syntelly</i> platform.

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“…28 Recently, first MYC/WDR5 protein-protein interface inhibitors have been developed. 15,29 The WDR5 WIN site, located opposite the MYC binding site, is required for WDR5 chromatin recruitment and interaction with KMT2 enzymes, and MLL1 is a particularly dependent on this interaction. The small molecule antagonist OICR-9429 for instance binds to the WIN site of WDR5, and efficiently disrupts its interaction with MLL1.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Evaluation of WD-repeat containing protein 5 (WDR5) degraders

Doelle

Adhikari

Kraemer

et al. 2021

Preprint

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Histone H3K4 methylation serves as post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat containing protein 5 (WDR5) that has also been associated with controlling long non-coding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic function. This study presents the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.

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Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5–MYC Protein–Protein Interaction

Cited by 47 publications

References 54 publications

Phage-Display Based Discovery and Characterization of Peptide Ligands against WDR5

Phage-Display Based Discovery and Characterization of Peptide Ligands against WDR5

Image2SMILES: Transformer-based Molecular Optical Recognition Engine

Design, Synthesis and Evaluation of WD-repeat containing protein 5 (WDR5) degraders

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