Enzyme inhibitor
This cell cycle-inhibiting flavone and anticancer agent (FW = 438.30 g/mol;
CAS 920113-03-7), also named 2- (2-chlorophenyl) -5,7-dihydroxy-8-
[ (2R,3S) -2- (hydroxymethyl) -1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-
one, targets the Cyclin-Dependent Kinases CDK1 (IC50 = 79 nM), CDK4
(IC50 = 63 nM) and CDK9 (IC50 = 20 nM). p276-00 showed potent
antiproliferative effects against various human cancer cell lines (IC50 values
ranging from 300 to 800 nmol/L), but has little effect on cultured fibroblasts
. A significant down-regulation of cyclin D1 and Cdk4 and a decrease in
Cdk4-specific pRb Ser phosphorylation is observed. P276-00 produces
potent inhibition of Cdk4-D1 activity that is competitive with ATP, and not
with retinoblastoma protein. The compound also induced apoptosis in
human promyelocytic leukemia (HL-60) cells, as evidenced by the
induction of caspase-3 and DNA ladder studies. In 22 human cancer
xenografts, P276-00 is approximately 26x more potent than cisplatin, and is
also active against cisplatin-resistant tumors of central nervous system,
melanoma, prostate, and renal cancers. Synchronized human non-small
cell lung carcinoma (H-460) and human normal lung fibroblast (WI-38)
cells are arrested in G1.
