Preclinical development of Lor-253, a novel anticancer drug candidate that functions by modulating intracellular labile zinc homeostasis leading to cell cycle arrest

5715 Cellular zinc has structural and regulatory functions. The structural functions involve a highly stable association of zinc to folded protein domains, while a more dynamic, exchangeable labile zinc pool is involved in regulatory functions. Reduction of labile zinc has been associated with the induction of apoptosis, decreased cell proliferation and altered cell cycle progression in several cancer cell types. Lor253 is a novel anticancer drug candidate selected from a library of 2-indolyl imidazol [4,5-d] phenanthroline derivatives with zinc chelation properties. Lor253 shows selective growth inhibition of cancer cell lines compared to primary cultures of normal cells, demonstrating tumor-type selectivity of colon cancer, leukemia, non-small cell lung cancer and prostate cancer cells in vitro . Mechanism of action studies indicate that Lor253 reduces the levels of intracellular labile zinc leading to cell cycle arrest, through two main mechanisms. The first involves the induction Kruppel like factor 4 (KLF-4). G1/S cell cycle arrest is mediated by KLF-4, which represses the transcription of cyclin D1 by displacing the positive regulator Sp1 from the cyclin D1 promoter. The second mechanism involves the down regulation of the zinc-sensor, metal transcription factor 1 (MTF-1), altering a previously unidentified cell cycle regulatory pathway that consists of the direct transcriptional activation of the cyclin D1 promoter by MTF1. Lor-253 has been formulated for intravenous administration as HCl salt (Lor253-HCl), showing potent anti-tumor efficacy in xenograft models of human colon carcinoma (HT-29) and non-small cell lung cancer (H460) in CD-1 nude mice. The minimum effective dose was 2 mg/kg administrated by IV bolus injection continuously for 5 days, with a maximum tolerated dose of 30 mg/kg. Exploratory bioavailability studies demonstrated a favorable pharmacokinetic profile in rats, and a rapid biodistribution into tissues of CD-1 nude mice harboring NSCLC H460 xenografted tumors, with significantly higher accumulation and longer residence in lungs (80% of dose at 0.25 h and 3% of dose at 24h) and colon (0.2% of dose at 0.25h and 0.1% of dose at 24h) compared to xenografted tumors (0.1% of dose at 0.25h and 0.02% of dose at 24h). These results indicate the potential for significantly higher efficacy of Lor253 in orthotopic models and clinical cases of colon carcinoma and lung carcinoma. Preclinical toxicology and toxicokinetic studies are in progress, as well as the preparation and design of a phase I clinical trial.