ArticleNature communications2021
Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 45 citations in OpenAlex.
- Anagrelide Remodels the PDE3A-SLFN12 Interactome to Associate with Translation Initiation Machinery in Cancer Cell Lines.Molecular & cellular proteomics : MCP · 2026Article
- Preclinical response of uveal melanomas to the velcrin compound, BAY 2666605.Molecular cancer therapeutics · 2026Article
- Pan-cancer ex vivo target evaluation of phosphodiesterase 3 A (PDE3A).Journal of molecular medicine (Berlin, Germany) · 2026Article
- Ubiquitin-dependent recruitment of SLFN11 to chromatin is regulated by deubiquitinase (DUB) and RNF168.Research square · 2026Article
- The Role of PDE3A in Cancer.ACS omega · 2026Review
- Pharmacokinetic profile andDrug delivery · 2025Article
- A scalable reinforcement learning approach for screening large peptide libraries for bioactive peptide discovery.Nature communications · 2025Article
- Epigenetic and Post-Translational Regulation of Schlafen Family Expression and Their Differential Methods of Regulating Proteins.International journal of molecular sciences · 2025Review
- Schlafen 12 Modulation and Targeting in Acute Myeloid Leukemia.Cancer research communications · 2025Article
- SLFN11, far from being limited to responding to cancer DNA damage.Clinical and experimental medicine · 2025Review
- Structural and functional characterization of human SLFN14.Nucleic acids research · 2025Article
- Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia.Leukemia · 2025Article
- Establishment and validation of a prognostic model based on vasculogenic mimicry-related gene clustering in ovarian cancer.Frontiers in oncology · 2025Article
- First-in-Human Dose-Escalation Study of the First-in-Class PDE3A-SLFN12 Complex Inducer BAY 2666605 in Patients with Advanced Solid Tumors Coexpressing SLFN12 and PDE3A.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Phosphorylation-mediated conformational change regulates human SLFN11.Nature communications · 2024Article
- Discovery of BAY 2666605, a Molecular Glue for PDE3A and SLFN12.ACS medicinal chemistry letters · 2024Article
- A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Overview of Structural and Functional Insights of SLFN12 Associated With Different Diseases.Cureus · 2024Review
- Recent Advances in Automated Structure-Based De Novo Drug Design.Journal of chemical information and modeling · 2024Review
- Research progress of the SLFN family in malignant tumors.Frontiers in oncology · 2024Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-β-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus "gluing" the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts.
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