Abstract 1626: Novel trisubstituted triazoles modeled from naltrindole inhibit the proliferation of human multiple myeloma cells

Abstract

Abstract Multiple myeloma (MM) is an invasive plasma cell neoplasm of malignant cells that proliferate in the bone marrow. This incurable cancer is responsible for 10% of all hematological malignancies. The American Cancer Society estimated that in 2011, 11,400 men and 9,120 women were diagnosed with MM in the United States, and 5,770 men and 4,840 women died of the disease. MM is characterized by monoclonal gammopathy, destructive bone disease, renal failure, hypercalcemia, and hematological dysfunction. The molecular pathogenesis of MM is complex. Gene expression profiling and deep genome sequencing has revealed that in many cases, chromosome translocations result in overexpression of growth regulatory genes via their juxtaposition to the immunoglobulin heavy chain locus, activation of the NF-kB pathway, activation of MYC, FGFR3, KRAS, NRAS, and loss of function mutations in the histone H3K27 demethylase gene UTX. Despite the development of new treatment agents in the last decade, including lenalidomide (an immunomodulatory drug) and bortezomib (a proteasome inhibitor), the five-year relative survival rate for MM is approximately 40%. Obviously, there is a great need for additional treatment options. Naltrindole (Nti) is a synthetic alkaloid with the pharmacological profile of a selective delta opioid receptor antagonist. Nti has also been reported to be a potent immunosuppressant. Nti suppresses the allogeneic mixed lymphocyte reaction in vitro and inhibits renal graft rejection in vivo. Subsequently, it was reported that Nti retains its immunosuppressive activity in triple mu/delta/kappa opioid receptor knockout mice, revealing a non-opioid receptor target for the immunosuppressant activity of Nti (Gaveriaux-Ruff et al., 2001). We reported previously (Mundra et al., J. Pharmacol. Exp. Ther. 342: 273-287, 2012), that Nti inhibited human MM cell proliferation in vitro and in a murine xenograft model in vivo, by interaction with a non-opioid receptor target. In the present study, we describe a novel series of triazole-based ligands derived from Nti by rational design (see Peng et al., Bioorgan. & Med. Chem. 17: 6442-6450, 2009) that competed for specific 3H-Nti binding to human U266 MM cells and inhibited MM cell proliferation in vitro. To date, 17 trisubstituted triazoles have been evaluated for their ability to inhibit MM cell proliferation. Following incubation with U266 MM cells for 72 h, the majority of MM triazoles exhibited EC50's in the 10-60 micromolar range. However, 3 of the triazoles displayed EC50's of 300-400 nM. It is hoped that further modification of these lead compounds will yield drugs with even greater efficacy. This study provides a rationale basis for further evaluation of this series of triazoles as anti-MM therapeutic agents. Citation Format: William J. Welsh, Youyi Peng, Jyoti Joshi Mundra, Julianne F. Avrutik, Thomas C. Yoon, Andrew M. Meillier, Richard D. Howells. Novel trisubstituted triazoles modeled from naltrindole inhibit the proliferation of human multiple myeloma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1626. doi:10.1158/1538-7445.AM2014-1626