Mutant p53 targeting by the low molecular weight compound STIMA-1.
Reactivation of mutant p53 in human tumor cells should induce cell death by apoptosis and thus eliminate the tumor. Several small molecules that reactivate mutant p53 have been identified. Here we show that STIMA-1, a low molecular weight compound with some structural similarities to the previously identified molecule CP-31398, can stimulate mutant p53 DNA binding in vitro and induce expression of p53 target proteins and trigger apoptosis in mutant p53-expressing human tumor cells. Human diploid fibroblasts are significantly more resistant to STIMA-1 than mutant or wild type p53-carrying tumor cells. STIMA-1 may provide new insights into possible mechanisms of mutant p53 reactivation and thus facilitate the development of novel anticancer drugs that target mutant p53-carrying tumors.
Zache
Nicole
N
Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska University Hospital, Stockholm, Sweden.
Lambert
Jeremy M R
JM
Rökaeus
Nina
N
Shen
Jinfeng
J
Hainaut
Pierre
P
Bergman
Jan
J
Wiman
Klas G
KG
Bykov
Vladimir J N
VJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D005347:Fibroblasts; D006801:Humans; D008970:Molecular Weight; D050505:Mutant Proteins / Q000187:drug effects; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D052999:Quinazolinones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D014753:Vinyl Compounds / Q000494:pharmacology*
C541990:2-vinylquinazolin-4-(3H)-one; D000970:Antineoplastic Agents; D050505:Mutant Proteins; D052999:Quinazolinones; D016159:Tumor Suppressor Protein p53; D014753:Vinyl Compounds; D004247:DNA