Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound
Vladimir J.N. Bykov1, Natalia Issaeva1, Alexandre Shilov1, 2, Monica Hultcrantz1, Elena Pugacheva3, Peter Chumakov3, Jan Bergman4, Klas G. Wiman1
& Galina Selivanova1
1
Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden
2
Institute of Cytology and Genetics, RAN, Novosibirsk, Russia
3
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
4
Department of Biosciences at Novum, Karolinska Institutet, Novum, Huddinge, Sweden
The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of low-molecular-weight compounds in order to identify compounds that can restore wild-type function to mutant p53. We found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53. This molecule, named PRIMA-1, restored sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. PRIMA-1 rescued both DNA contact and structural p53 mutants. In vivo studies in mice revealed an antitumor effect with no apparent toxicity. This molecule may serve as a lead compound for the development of anticancer drugs targeting mutant p53.
