Testing novel pyrimidinyl rexinoids: A new paradigm for evaluating rexinoids for cancer prevention

Di Zhang, Ana S. Leal, Sarah Carapellucci, Pritika H. Shahani, Jaskaran S. Bhogal, Samir Ibrahim, San Raban, Peter Jurutka, Pamela Marshall, Michael B. Sporn, Carl Wagner, Karen T. Liby

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Abstract

Rexinoids, selective ligands for retinoid X receptors inflammatory activities of rexinoids. We reveal new (RXR), have shown promise in preventing many types immunomodulatory actions of the above rexinoids, of cancer. However, the limited efficacy and undesir-especially their ability to diminish the percentage of able lipidemic side-effects of the only clinically macrophages and myeloid-derived suppressor cells in approved rexinoid, bexarotene, drive the search for the lung and to redirect activation of M2 macro-new and better rexinoids. Here we report the evalu-phages. The rexinoids also potently inhibit critical ation of novel pyrimidinyl (Py) analogues of two inflammatory mediators including IL6, IL1b, CCL9, known chemopreventive rexinoids, bexarotene (Bex) and nitric oxide synthase (iNOS) induced by lipo- and LG100268 (LG268) in a new paradigm. We show polysaccharide. Moreover, in vitro iNOS and SREBP that these novel derivatives were more effective agents (sterol regulatory element-binding protein) induction than bexarotene for preventing lung carcinogenesis assays correlate with in vivo efficacy and toxicity, induced by a carcinogen. In addition, these new respectively. Our results not only report novel pyrim-analogues have an improved safety profile. PyBex idine derivatives of existing rexinoids, but also caused less elevation of plasma triglyceride levels than describe a series of biological screening assays that bexarotene, while PyLG268 reduced plasma choles-will guide the synthesis of additional rexinoids. Fur-terol levels and hepatomegaly compared with ther progress in rexinoid synthesis, potency, and safe-LG100268. Notably, this new paradigm mechanistity should eventually lead to a clinically acceptable and cally emphasizes the immunomodulatory and anti-useful new drug for patients with cancer.

Original languageEnglish (US)
Pages (from-to)211-224
Number of pages14
JournalCancer Prevention Research
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2019

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhang, D., Leal, A. S., Carapellucci, S., Shahani, P. H., Bhogal, J. S., Ibrahim, S., Raban, S., Jurutka, P., Marshall, P., Sporn, M. B., Wagner, C., & Liby, K. T. (2019). Testing novel pyrimidinyl rexinoids: A new paradigm for evaluating rexinoids for cancer prevention. Cancer Prevention Research, 12(4), 211-224. https://doi.org/10.1158/1940-6207.CAPR-18-0317