Project Summary
Bexarotene is a potent and selective retinoid X receptor (RXR) agonist (rexinoid) that is FDA-approved as an
oral antineoplastic drug for cutaneous T-cell lymphoma (CTCL), but has also been explored in the treatment of
other cancers. However, bexarotene only has ~45% response rate as a systemic therapy in later stages of CTCL,
and while the response rate appears to improve at higher doses, there are dose-limiting toxicities associated
with treatment. We propose to employ rational drug design to synthesize ~50 novel rexinoids (1-21 and 52-80 in
the Research Plan) which display unique RXR binding properties that may render these analogs superior in
biological potency and specificity, compared to bexarotene, as treatments for CTCL. Previously, we synthesized
a panel of unique rexinoids with a variety of characteristics, including some analogs with superior efficacy and
less severe side-effects relative to bexarotene. Utilizing our knowledge-base of previous rexinoids developed,
tested, and validated by our group, we propose to synthesize a new suite of compounds which will be tested in
a series of assays that contribute to a Biopotency Index Analysis (BIA) score. The BIA has been used to rank
some of our existing compounds, and the ~50 new analogs we propose to develop are based on the structures
of rexinoids with the highest BIA values. The BIA score is composed of several components that can be
benchmarked to bexarotene or other target rexinoids (e.g.,NEt-TMN), including EC50 value, RXRE activation,
modulation of anti-cancer gene expression, apoptotic effects, and anti-proliferative potency. The ~50 new
analogs will be tested to assign BIA values. To determine RXR activation, we will assess each analog in a
comprehensive panel of bioassays. We will first test the proposed rexinoid molecules in RXR yeast and
mammalian two hybrid assays, as well as DNA-based (RXRE) assays to screen for RXR homodimer binding.
Those analogs that display RXR binding/homodimerization will be further evaluated via testing of their
modulation of anti-cancer genes (COX-2, DEPP, DEC2, IGFPD-6, etc.) and apoptotic genes (HDAC1, IkK, BIRC-
5, BO, etc.). The ~50 new rexinoids will also be assessed in apoptosis and proliferation assays in patient-derived
CTCL cell lines (e.g., Hut78). The 3 rexinoids with the best BIA profiles will then be scaled up for testing in a
novel mouse model of CTCL versus bexarotene and a vehicle control. Using interleukin-15 transgenic (IL-15tg)
mice, we will determine the in vivo safety, tolerability and efficacy of selected rexinoids in CTCL. IL-15tg mice
exhibit features of human CTCL, namely, cutaneous lesions characterized by erythematous plaques/patches,
erythroderma, and pruritus compared to wild-type controls. Collectively, this approach will allow us to synthesize
~50 additional RXR agonists that may exhibit superior gene expression profiles that drive anti-cancer pathways
in CTCL and then to validate this with in vitro and in vivo CTCL models. Our interdisciplinary and student-
centered approach integrates medicinal chemistry, modeling, and a suite of biological assays to amplify
our successful strategy of creating novel rexinoid pharmacotherapies suitable for clinical translation.
