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    GENE:

    PDE3A (Phosphodiesterase 3A)

    i
    Other names: PDE3A, Phosphodiesterase 3A, CGMP-Inhibited 3',5'-Cyclic Phosphodiesterase A, CGI-PDE, Cyclic GMP-Inhibited Phosphodiesterase A, Phosphodiesterase 3A, CGMP-Inhibited, CGI-PDE A, CAMP Phosphodiesterase, Myocardial CGMP-Inhibited, CGI-PDE-A, HTNB
    4ms
    Schlafen 12 modulation and targeting in acute myeloid leukemia. (PubMed, Cancer Res Commun)
    In addition, velcrin treatment suppressed clonogenic capacity of primitive leukemic progenitors and significantly extended survival in a mouse AML xenograft model. Taken together, these findings establish an important role of SLFN12 in leukemogenesis and raise the potential for the use of velcrins as a therapeutic strategy for AML.
    Journal
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    PDE3A (Phosphodiesterase 3A)
    8ms
    Phosphodiesterase 3 A expression in gastrointestinal stromal tumors. (PubMed, Virchows Arch)
    GISTs, with their consistently high PDE3A expression, are a promising target for PDE3A-targeted therapies. This method may also aid in stratifying patients in cancers where PDE3A expression is less common.
    Journal
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    KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDE3A (Phosphodiesterase 3A)
    1year
    Pharmacokinetic profile and in vivo anticancer efficacy of anagrelide administered subcutaneously in rodents. (PubMed, Drug Deliv)
    The SC formulation also significantly reduced tumor volumes and demonstrated dose-dependent histological responses, nearly eradicating tumor tissue in 11 days with the highest dose. These findings suggest that the SC slow-release formulation maintains stable drug concentrations during treatment, potentially improving therapeutic efficacy at the target site.
    PK/PD data • Preclinical • Journal
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    PDE3A (Phosphodiesterase 3A)
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    KIT exon 9 mutation
    over1year
    First-in-human dose escalation study of the first-in-class PDE3A-SLFN12 complex inducer BAY 2666605 in patients with advanced solid tumors co-expressing SLFN12 and PDE3A. (PubMed, Clin Cancer Res)
    Despite the decreased PDE3A enzymatic inhibition profile of BAY 2666605, the occurrence of thrombocytopenia in treated patients, an on-target effect of the compound, precluded the achievement of a therapeutic window, consequently leading to trial termination.
    P1 data • Journal • Metastases
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    PDE3A (Phosphodiesterase 3A)
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    PDE3A overexpression
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    BAY2666605
    over1year
    Discovery of BAY 2666605, a Molecular Glue for PDE3A and SLFN12. (PubMed, ACS Med Chem Lett)
    More analogs were prepared and tested with the goal of increasing metabolic stability and decreasing PDE3 inhibition while maintaining the cellular activity of BRD9500. This led to the discovery of BAY 2666605, a compound optimized for clinical testing.
    Journal
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    PDE3A (Phosphodiesterase 3A)
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    BAY2666605
    over1year
    Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia. (PubMed, Leukemia)
    In vivo combination treatment of leukemic animals with high PDE3A expression significantly reduced leukemia burden and prolonged survival time compared with single-drug and vehicle control treatments. Our findings suggest that combined ANA and IDA treatment is an innovative and promising therapeutic strategy for AML patients with high PDE3A expression.
    Journal
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    CASP3 (Caspase 3) • PDE3A (Phosphodiesterase 3A) • GSDME (Gasdermin E)
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    PDE3A overexpression
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    idarubicin hydrochloride
    over1year
    Personal Genetic-Hypertension Odyssey From Phenotypes to Genotypes and Targets. (PubMed, Hypertension)
    The scope of this project has elucidated genetic mechanisms important to cartilage development, possibly cancer metastases, and findings relevant to cardiovascular regulation via systemic vascular resistance. For our team, the project was an educational/scientific adventure over a professional lifetime.
    Review • Journal
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    PDE3A (Phosphodiesterase 3A)
    over1year
    Velcrin molecular glues induce apoptosis in glioblastomas with high PDE3A and SLFN12 expression. (PubMed, Neurooncol Adv)
    We also determined that the velcrins BAY 2666605 and BRD3800 induce tumor regression in subcutaneous glioblastoma PDX models. Velcrins have antitumor activity in preclinical models of glioblastoma, warranting further investigation as potential therapeutic agents.
    Journal
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    PDE3A (Phosphodiesterase 3A) • BRD3 (Bromodomain Containing 3)
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    BAY2666605
    over1year
    Novel genetic alterations in liver cancer distinguish distinct clinical outcomes and combination immunotherapy responses. (PubMed, Front Pharmacol)
    Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.
    Clinical data • Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
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    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • RB1 (RB Transcriptional Corepressor 1) • BAP1 (BRCA1 Associated Protein 1) • KMT2D (Lysine Methyltransferase 2D) • MSH2 (MutS Homolog 2) • KMT2C (Lysine Methyltransferase 2C) • FAT1 (FAT atypical cadherin 1) • NOTCH3 (Notch Receptor 3) • FAT3 (FAT Atypical Cadherin 3) • ZFHX3 (Zinc Finger Homeobox 3) • KDM5D (Lysine Demethylase 5D) • PDE4DIP (Phosphodiesterase 4D Interacting Protein) • LATS1 (Large Tumor Suppressor Kinase 1) • PDE3A (Phosphodiesterase 3A) • SYNE1 (Spectrin Repeat Containing Nuclear Envelope Protein 1) • MYO18A (Myosin XVIIIA) • PTPRZ1 (Protein Tyrosine Phosphatase Receptor Type Z1)
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    Avastin (bevacizumab)
    over1year
    A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors. (PubMed, Clin Cancer Res)
    These findings suggest that OPB-171775, with its significant efficacy, could potentially serve as a novel and effective treatment option for advanced GISTs, particularly those resistant to TKIs.
    Journal • Stroma
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    KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • PDE3A (Phosphodiesterase 3A)
    over1year
    METTL3's role in cervical cancer development through m6A modification. (PubMed, FASEB J)
    METTL3 catalyzed m6A modification on PDE3A mRNA through YTH domain family protein 3 (YTHDF3). Our study indicated the mechanism of m6A modification in CC and suggested the METTL3/YTHDF3/PDE3A axis as a potential clinical target for CC treatment.
    Journal
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    PDE3A (Phosphodiesterase 3A) • METTL3 (Methyltransferase Like 3) • YTHDF3 (YTH N6-Methyladenosine RNA Binding Protein F3)
    almost2years
    Genome-wide 5-hydroxymethylcytosines in circulating cell-free DNA as noninvasive diagnostic markers for gastric cancer. (PubMed, Gastric Cancer)
    The characteristics of 5-hydroxymethylcytosine in cell free DNA are specific to gastric cancer patients, and the diagnostic model constructed by five genes' 5-hydroxymethylcytosine features could effectively identify gastric cancer patients.
    Journal
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    PDE3A (Phosphodiesterase 3A) • STXBP5 (Syntaxin Binding Protein 5)