title: Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics.
abstract: 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.
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: de Waal
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Lewis
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Rees
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Aviad
authors.identifier: http://orcid.org/0000-0002-3797-1877
authors.initials: A
authors.lastname: Tsherniak
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wu
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Choi
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Gechijian
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Hartigan
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Faloon
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hickey
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tolliday
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
authors.forename: Angela N
authors.initials: AN
authors.lastname: Koehler
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Schenone
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Burgin
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Stuart L
authors.identifier: http://orcid.org/0000-0003-1922-7558
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D003603:Cytotoxins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D023281:Genomics; D006801:Humans; D015151:Immunoblotting; D009369:Neoplasms / Q000628:therapy*; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000608111:6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D011724:Pyridazines; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3