Abstract C040: INTH-454, a p300/CBP interactome modulator, targets multiple pathogenesis factors in solid tumors and induces strong anti-proliferative effects in vitro and in vivo as single agent

• Published in: Molecular cancer therapeutics 2019-12, Vol.18 (12_Supplement), p.C040-C040
• Main Authors: Cattori, Valentino, Hentsch, Bernd, Kessler, Ulrich
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-19-C040

Background: INTH-454 is a novel rationally designed ligand of the CH1/TAZ1 domain of p300/CBP, two closely related paralog transcription co-activators crucially involved in cancer cell proliferation and tumor progression. Here, we report the in vitro and in vivo characterization of INTH-454 in preclinical models of castration-resistant prostate (CRPC) and gastrointestinal (GI) cancer. Methods: The anti-proliferative effects of INTH-454 were assessed in colon, gastric and prostate cancer cells harboring wild type, mutant or no p53 protein followed by cell cycle analysis, beta-galactosidase staining and caspase activation assays. Levels of p53, acetylated p53 and p21 were determined by Western blotting. The impact of INTH-454 on ubiquitination/degradation of p53 and p21 was investigated and pharmacodynamic and anti-tumoral effects of INTH-454 were illustrated in cell line and patient derived xenograft models of prostate and GI cancer. Results: INTH-454 exhibited anti-proliferative effects at low nanomolar concentrations in all cell lines inducing strong cell cycle arrest followed by senescence or cell death. Levels of p21 were stably increased independent of p53-status and the amount of both, total ubiquitinated protein and ubiquitinated p53, was significantly decreased in treated cells. Oral administration of INTH-454 triggered strong inhibition of tumor growth in xenograft mouse models of CRPC and GI cancer up to tumor eradication at well tolerated doses. Analysis of tumor tissue by immunohistochemistry and Western blotting confirmed the in vitro results and illustrated additional pharmacodynamic effects on disease specific markers such as reduction of VEGF and PSA. Conclusions: Blockage of the CH1/TAZ1 domain of p300/CBP has a profound effect on cell cycle regulation in cancer cells. INTH-454 causes cell cycle arrest through stabilization/overexpression of p21 in a p53-dependent and -independent manner followed by either cell death or senescence and sustained anti-tumoral effects in xenograft models of prostate and gastrointestinal carcinomas. Citation Format: Valentino Cattori, Bernd Hentsch, Ulrich Kessler. INTH-454, a p300/CBP interactome modulator, targets multiple pathogenesis factors in solid tumors and induces strong anti-proliferative effects in vitro and in vivo as single agent [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AAC