Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics
Open accessAbstract
High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the gene PDE3A, encoding phosphodiesterase 3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells, whereas others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggestive of a neomorphic activity. Coexpression of SLFN12 with PDE3A correlates with DNMDP sensitivity, whereas depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery.
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DNMDP and related small molecules induce interaction between PDE3A and SLFN12, leading to a cytotoxic effect in cancer cells with high expression of both proteins.
“DNMDP and related small molecules induce interaction between the phosphodiesterase PDE3A and SLFN12 (Fig. 3C and 6), leading to a cytotoxic effect in cancer cells with high expression of both proteins.75,105”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [105]
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References 52 · Cited by 96
- Authors
- de Waal, L., Lewis, T. A., Rees, M. G., Tsherniak, A., Wu, X., Choi, P. S., Gechijian, L., Hartigan, C., Faloon, P. W., Hickey, M. J., Tolliday, N., Carr, S. A., Clemons, P. A., Munoz, B., Wagner, B. K., Shamji, A. F., Koehler, A. N., Schenone, M., Burgin, A. B., Schreiber, S. L., Greulich, H., & Meyerson, M.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Greulich, Heidi
- Meyerson, Matthew
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2015-12-14
- Volume
- 12
- Issue
- 2
- Pages
- 102-108
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4718766
- OpenAlex
- W2273218209
- Cited by
- 96
- References
- 52
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 10 · 2023: 9 · 2022: 13 · 2021: 9 · 2020: 9 · 2019: 10 · 2018: 8 · 2017: 8 · 2016: 4
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (U54HG005032)
- National Cancer Institute (U01CA176152, P30CA014051, R35CA197568)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- PDE3A, SLFN12, SIRT7, phenotypic screening, cancer cell lines, drug resistance, anticancer drug discovery, small molecule drug discovery
- MeSH terms
- Cell Line, Cell Survival, Cytotoxins, Enzyme Activation, Enzyme Inhibitors, Humans, Neoplasms, Pyridazines, Immunoblotting, Drug Delivery Systems, Genomics, Cell Line, Tumor, Cyclic Nucleotide Phosphodiesterases, Type 3
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