Testing Novel Pyrimidinyl Rexinoids: A New Paradigm for Evaluating Rexinoids for Cancer Prevention

Abstract

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

The novel rexinoid MSU-42011 is effective for the treatment of preclinical Kras-driven lung cancer

“…have confirmed that the iNOS assay correlates with in vivo efficacy 21 , few investigators have used the induction of SREBP in vitro as a biomarker to predict the ability of novel rexinoids to increase triglycerides in vivo. Elevated triglycerides are a side-effect found with many RXR agonists in preclinical models and by bexarotene in humans 13,14 .…”

“…Elevated triglycerides are a side-effect found with many RXR agonists in preclinical models and by bexarotene in humans 13,14 . In order to validate the utility of SREBP as an in vitro biomarker for increased triglycerides in vivo, established rexinoids known to induce hypertriglyceridemia (bexarotene, LG100268, and IRX194204) and LG101506 (a rexinoid that does not induce hypertriglyceridemia in vivo) 21,42 were directly compared to evaluate their ability to induce SREBP protein in vitro ( Fig. 1A).…”

“…To overcome these challenges, we have synthesized new rexinoids and optimized a set of in vitro screening assays that correlate with efficacy and toxicity in vivo 21 . This screening system quantifies inhibition of the inflammatory mediator inducible nitric oxide synthase (iNOS) and induction of sterol regulatory element binding protein (SREBP), involved in triglyceride synthesis.…”

“…Inflammation plays an important role in carcinogenesis [22][23][24] and creates a favorable microenvironment in which tumors can thrive 25 . The ability of rexinoids to inhibit lipopolysaccharide-induced production of nitric oxide (NO) in RAW264.7 macrophage-like cells directly correlates with anti-cancer activity in the clinically relevant A/J mouse model of lung cancer 21 . SREBP is a transcription factor that regulates cellular lipid metabolism and homeostasis 26 and therefore is a surrogatge in vitro biomarker for predicting hypertriglyceridemia.…”

The exploration of new therapeutic targets for HPV‐negative head and neck squamous cell cancer through the construction of a ceRNA network and immune microenvironment analysis

“…Bexarotene, a RXR stimulator, has been applied in the treatment of cutaneous T‐cell lymphoma. Bexarotene can stimulate the apoptosis of tumor cells and plays an immunomodulatory role, especially in the aspect of reducing macrophages in the tumor microenvironment …”