ArticleProceedings of the National Academy of Sciences of the United States of America2020
Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed.
- A Versatile DNA-Encoded Library Platform for the Discovery of Highly Cooperative Chemical Inducers of Proximity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Ubiquitin family as novel protein partners for molecular glues.npj drug discovery · 2026Review
- MG132-mediated inhibition of rabies virus replication via the Nrf2/SQSTM1/PINK1/Parkin autophagy pathway.Virology journal · 2026Article
- Discovery of molecular glues that bind FKBP12 and structurally distinct targets using DNA-encoded libraries.Nature communications · 2026Article
- Molecular Glues Stabilize Water-Mediated Hydrogen Bonds in Ternary Complexes.Chemphyschem : a European journal of chemical physics and physical chemistry · 2026Article
- Identification and characterization of binders to a cryptic and functional pocket in KRAS.Nature communications · 2025Article
- The Role of Nucleotide Sequencing in Natural Product Drug Discovery.Journal of natural products · 2025Review
- Emerging opportunities in the rewiring of biology through proximity inducing small molecules.RSC medicinal chemistry · 2025Article
- Target agnostic cellular screening in the era of chemically induced proximity.RSC medicinal chemistry · 2025Review
- Targeted genome mining with GATOR-GC maps the evolutionary landscape of biosynthetic diversity.Nucleic acids research · 2025Article
- Nondegradative Synthetic Molecular Glues Enter the Clinic.ChemMedChem · 2025Review
- Research advancements in molecular glues derived from natural product scaffolds: Chemistry, targets, and molecular mechanisms.Chinese herbal medicines · 2025Review
- Development of an FKBP12-recruiting chemical-induced proximity DNA-encoded library and its application to discover an autophagy potentiator.Cell chemical biology · 2025Article
- Targeted genome mining with GATOR-GC maps the evolutionary landscape of biosynthetic diversity.bioRxiv : the preprint server for biology · 2025Article
- Genomic Discovery and Structure-Activity Exploration of a Novel Family of Enzyme-Activated Covalent Cyclin-Dependent Kinase Inhibitors.Journal of medicinal chemistry · 2024Article
- Assessing and harnessing updated polyketide synthase modules through combinatorial engineering.Nature communications · 2024Article
- Critical analysis of polycyclic tetramate macrolactam biosynthetic gene cluster phylogeny and functional diversity.Applied and environmental microbiology · 2024Article
- Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.Cancer discovery · 2024Article
- Article
- SARS-CoV-2, periodontal pathogens, and host factors: The trinity of oral post-acute sequelae of COVID-19.Reviews in medical virology · 2024Review
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Authors and funding
26 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.
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