Discovery of new pyridoacridine alkaloids from Lissoclinum cf. badium that inhibit the ubiquitin ligase activity of Hdm2 and stabilize p53.
Compounds that stabilize p53 could suppress tumors providing a additional tool to fight cancer. Mdm2, and the human ortholog, Hdm2 serve as ubiquitin E3 ligases and target p53 for ubiquitylation and degradation. Inhibition of Hdm2 stabilizes p53, inhibits cell proliferation and induces apoptosis. Using HTS to discover inhibitors, we identified three new alkaloids, isolissoclinotoxin B, diplamine B, and lissoclinidine B from Lissoclinum cf. badium. Lissoclinidine B inhibited ubiquitylation and degradation of p53, and selectively killed transformed cells harboring wild-type p53, suggesting this compound could be used to develop new treatments.
Clement
Jason A
JA
Molecular Targets Development Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702-1201, USA.
Kitagaki
Jirouta
J
Yang
Yili
Y
Saucedo
Carrie J
CJ
O'Keefe
Barry R
BR
Weissman
Allan M
AM
McKee
Tawnya C
TC
McMahon
James B
JB
D000166:Acridines / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D010618:Phenanthrolines / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D014561:Urochordata / Q000737:chemistry*
D000166:Acridines; D000470:Alkaloids; D004791:Enzyme Inhibitors; D010618:Phenanthrolines; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C475900:pyridoacridine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2