Preferred Label : Adenosine A2A Receptor Antagonist/Phosphodiesterase 10A PBF-999;
NCIt synonyms : A2A/PDE-10A Inhibitor PBF-999;
NCIt related terms : PBF-999;
NCIt definition : An orally bioavailable inhibitor of both the adenosine A2A receptor (A2AR; ADORA2A)
and phosphodiesterase 10A (PDE-10A), with potential immunomodulating and antineoplastic
activities. Upon administration, A2A/PDE-10A inhibitor PBF-999 selectively binds to
and inhibits A2AR expressed on T-lymphocytes. This blocks tumor-released adenosine
from interacting with A2AR and prevents the adenosine/A2AR-mediated inhibition of
T-lymphocytes. This results in the proliferation and activation of T-lymphocytes and
stimulates a T-cell-mediated immune response against tumor cells. A2AR, a G protein-coupled
receptor, is highly expressed on the cell surfaces of T-cells and, upon activation
by adenosine, inhibits T-cell proliferation and activation. Adenosine is often overproduced
by cancer cells and plays a key role in immunosuppression. In addition, PBF-999 binds
to and inhibits the activity of PDE-10A, thereby preventing the degradation of cyclic
guanosine monophosphate (cGMP) and activates cGMP/cGMP-dependent protein kinase G
(PKG) signaling. This induces beta-catenin degradation and thereby prevents the translocation
of beta-catenin into the nucleus, and the beta-catenin-mediated induction of transcription
of survival proteins, such as cyclin D1 and survivin. It also suppresses RAS/RAF/mitogen-activated
protein kinase (MAPK) signaling. This induces apoptosis and inhibits the growth of
tumor cells in which PDE-10A is overexpressed. PDE-10A is a cGMP-degrading PDE isozyme
that is highly expressed in the brain and overexpressed in certain types of tumor
cells. Elevation of intracellular cGMP is known to inhibit tumor proliferation and
induce apoptosis. cGMP levels are low in cancer cells resulting from the overexpression
PDE-10A.;
UNII : DY6W3NQA36;
CAS number : 1620909-95-6;
Molecule name : PBF 999; PBF-999;
NCI Metathesaurus CUI : CL937074;
Origin ID : C157489;
UMLS CUI : C4763656;
Semantic type(s)
- concept_is_in_subset
