**1. Introduction**

Cancer-preventive agents are biologics, dietary supplements, nutrients or marketed drugs used to reduce the risk of developing cancer or prevent the recurrence of cancer [1]. The cancer-preventive actions of these agents are mediated by a variety of proposed mechanisms, which include inhibition of oxidative and inflammatory stress, immunomodulatory action, induction of cell differentiation and apoptosis, and inhibition of cell growth and angiogenesis. Hundreds of natural and synthetic compounds have been shown to inhibit cancer cell growth including vitamins (vitamins A, D, and E), organosulfur compounds (brassinin, sulforaphane,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and isothiocyanates), minerals (calcium and selenium), phytoestrogens (resveratrol), flavonoids (genistein and quercetin), synthetic compounds (retinoids, sulforamate, and prenylated flavonoid analogs) [2], and marketed drugs (tamoxifen, raloxifene, finasteride, aspirin, sulindac, difluoromethylornithine, and metformin) [3]. Drug development for cancer prevention imposes distinct challenges beyond those associated with drug development for cancer therapy. One of the challenges is that cancer preventive agents must have higher therapeutic index. Nevertheless, the potential to intervene prior to the cancer developing is an attractive strategy to fight cancers [4].

A novel class of anticancer agents that has demonstrated such qualities is the flexible heteroarotinoids (Flex-Hets). Flex-Hets, derived from the retinoids, have exhibited potential anticancer activities in various cancer cell lines, while displaying minimal toxicity to normal cells. Among these compounds, SHetA2 [(4-nitrophenyl)amino][2,2,4,4-tetramethylthiochroman-6-yl]amino]methane-thione) exhibited the greatest growth inhibitory efficacy and potency against various cancer cell lines and was chosen as a lead compound for further development [5–7]. SHetA2 has been shown to interfere with mortalin binding to p53 and p66 Src homologous-collagen homologue (p66shc) leading to apoptosis in cancer cells [8]. Furthermore, it has been shown to induce both intrinsic [9] and extrinsic apoptotic pathway [10], cause cell cycle arrest [11], induce differentiation [7], and inhibit angiogenesis [12] in cancer cells, while displaying negligible toxicity in animal models [13]. Hence, SHetA2 was regarded as a novel class of promising anticancer agent that selectively targeted the cancer cells. Consequently, it was evaluated in preclinical development for cancer prevention through the National Cancer Institute (NCI) Rapid Access to Intervention Development (RAID) and Rapid Access to Preventive Intervention Development (RAPID) program [6]. Studies in rats and dogs showed that no toxicity was observed in any of the tested dosage groups. The no-observed-adverse-effect-level (NOAEL) for SHetA2 was not established and was considered to be above 1500 mg/kg/day in dogs [13]. The therapeutic window for administrative safety with SHetA2 was determined to be 25- to 150-folds above *in vivo* effective doses. As a result, it is currently undergoing Phase-0 clinical trials through RAID [14]. This chapter will provide a comprehensive review of SHetA2, including its design and development, and possible molecular targets and mechanisms of action and its potential clinical applications, based on the literature published thus far.
