Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound

Abstract

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.

PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

“…The low molecular weight compounds PRIMA-1 and PRIMA-1 MET /APR-246 restore wild-type function to mutant p53 and trigger mutant p53-dependent apoptosis (Bykov et al, 2002b). As the DNA-binding domains of p53, p63 and p73 share high sequence homology, we hypothesized that PRIMA-1 MET might be active against mutant forms of p63 and p73 as well.…”

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

“…PRIMA-1 (for p53 reactivation and induction of massive apoptosis), the methylated analog PRIMA-1MET and MIRA-1 (for mutant p53 reactivation and induction of rapid apoptosis) have similar activity profiles (Bykov et al, 2002a(Bykov et al, , b, 2005a). Yet they are structurally unrelated and presumably affect mutant p53 through different mechanisms.…”

“…In contrast, PRIMA-1 and MIRA-1 were identified in a cellular screening for compounds that induce apoptosis selectively in human tumor cells expressing exogenous mutant p53 (Bykov et al, 2002a(Bykov et al, , 2005b. The compounds were shown to rescue wild-type conformation of mutant p53 proteins in vitro and induce expression of p53 target genes such as p21, MDM2 and/ or PUMA.…”

CDC20, a potential cancer therapeutic target, is negatively regulated by p53

“…Another approach is the identification of compounds or peptides that manipulate the p53 function. Several small molecular compounds were developed to restore mutant p53 conformation to wild type or to disrupt MDM2-p53 binding and increase the stability of p53 (Bykov et al, 2002;Issaeva et al, 2004). As a result of p53 inactivation, we considered that some p53-suppressive genes playing significant roles in carcinogenesis might be upregulated in cancer tissues.…”