Renal cell carcinomas (RCC) commonly retain wild-type but functionally inactive p53, which is repressed by an unknown dominant mechanism. To help reveal this mechanism, we screened a diverse chemical library for small molecules capable of restoring p53-dependent transactivation in RCC cells carrying a p53-responsive reporter. Among the compounds isolated were derivatives of 9-aminoacridine (9AA), including the antimalaria drug quinacrine, which strongly induced p53 function in RCC and other types of cancer cells. Induction of p53 by these compounds does not involve genotoxic stress and is mediated by suppression of NF-B activity. In contrast to agents that target I B kinase 2, 9AA and quinacrine can effectively suppress both basal and inducible activities of NF-B, representing inhibitors of a previously undescribed type that convert NF-B from a transactivator into a transrepressor, leading to accumulation of inactive nuclear complexes with unphosphorylated Ser-536 in the p65͞RelA subunit. p53 function in RCC can be restored by ectopic expression of a superrepressor of I B as effectively as by 9AA-derived compounds. These findings suggest that the complete or partial repression of p53 observed in many tumors can be the result of constitutive activation of NF-B. The results demonstrate, in principle, the possibility to kill cancer cells selectively through simultaneous inhibition of NF-B and activation of p53 by a single small molecule and suggest anticancer applications for the well known antimalaria drug quinacrine.anticancer treatment ͉ apoptosis ͉ chemical library ͉ quinacrine T he protein p53 controls genetic stability and reduces the risk of cancer through induction of growth arrest or apoptosis in response to DNA damage or deregulation of proto-oncogenes (1). The efficacy of p53 as a tumor-preventing factor is reflected by the high frequency of p53 loss, in at least 50% of human tumors, due to inactivating mutations (2). Understanding the mechanisms of functional inactivation of wild-type p53 in human tumors, for example, by overexpression of natural antagonists of p53, Mdm2, or the viral protein E6, helps to define prospective targets for treating cancer by restoring p53 function (3).We have recently shown that renal cell carcinomas (RCC), the most frequent and least curable type of kidney cancer, maintain wild-type but functionally inactive p53 (4). The mechanism of p53 repression in RCC is dominant, and therefore ''druggable,'' and different from that of all reported cases of p53 repression in tumors, suggesting the existence of an as-yet-unknown molecular target for restoring p53 function in cancer. As an approach to finding such factor(s), we have isolated a set of compounds that can restore p53 function in RCC and strongly activate p53 in many other types of cancer cells. Among the most effective compounds from this set were derivatives of 9-aminoacridine (9AA), including an old-known antimalaria drug quinacrine (QC). Analysis of the molecular mechanisms of action of 9AA and QC showed that p53 activat...

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We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A 2B receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2′-amino-4′-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding K i value of 112 nM. We explored the effects of both substituent-and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly nonselective adenosine receptor ligands with K i values in the micromolar range. Since no enhancement of A 2B receptor affinity of 38 was achieved, the previously reported pharmacophorebased searching strategy yielded the most potent and selective structurally-related hit in the database originally searched.