Abstract SY18-02: Targeting transcriptional regulators for simultaneous modulation of p53 and NF-κB in cancer treatment

Abstract

Abstract There are three advantages of phenotype-based versus traditional target-based drug discovery strategy. It (i) avoids placing premature focus on a target that may not be the optimal one, (ii) permits the biological system to drive the investigator towards the optimal target through the selection process and (iii) eliminates a number of pharmacological optimization steps by filtering out compounds with unacceptable toxicity or intracellular stability. We used cell phenotype-based readout to screen for chemicals capable of activation of dormant p53 in tumor cells. As a result, we isolated two classes of compounds that simultaneously inhibit NF-kappaB through previously unknown mechanism and activate p53 without causing any genotoxicity. These compounds appeared to have strong anticancer activity in all tested human tumor xenografts grown in mice and were named Curaxins. The mechanisms of activity of Curaxins involves targeting SSRP1, a component of “facilitate chromatin transcription” (FACT) complex, which is required for transcription from NF-kappaB-inducible promoters. In the presence of Curaxins, SSRP1 is trapped in chromatin thereby blocking NF-kappaB-mediated gene expression what results in CK2-mediated activation of p53 through its phosphorylation at a single C-terminal serine residue. Besides NF-kappaB, Curaxins suppress initiation of transcription driven by Heat Shock Factor-1 (HSF1), thereby blocking activation of cell response to proteotoxic stresses (heat shock response). Constitutive activation of NF-kappaB and HSF1 is frequently observed in tumors making them “addicted” to these pro-survival pathways. The mechanism of antitumor activity of Curaxins suggests their rational combinations with other cancer treatment approaches. For example, inhibition of HSF1 explains high antitumor efficacy of these compounds in tumor-bearing mice treated by Curaxins in combination with proteotoxic stress (local hyperthermia or proteotoxic drugs) Simultaneous targeting of three signal transduction pathways commonly deregulated in cancer (suppression of NF-kappaB and HSF1 and activation of p53) and lack of genotoxicity opening the opportunity for using Curaxins not only for safe chemotherapy but also for chemoprevention. In fact, efficacy of Curaxins as chemopreventive agents given in drinking water was demonstrated in the mouse model of spontaneous breast cancer (transgenic mice carrying MMTV promoter-driven expression of her2/neu). In summary, Curaxins are triple-targeted non-genotoxic anticancer drug candidates acting through the inhibition of SSRP1 function via non-genotoxic DNA binding. The Curaxin story indicates principle advantages of phenotype-driven “non-targeted” drug discovery strategy, which enables finding new anticancer targets and approaches that could not be predicted based on the preexisting knowledge. Citation Format: Katerina Gurova, Andrei V. Gudkov. Targeting transcriptional regulators for simultaneous modulation of p53 and NF-κB in cancer treatment [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY18-02