Triptolide and its pro-drug Minnelide target high-risk MYC amplified medulloblastoma in preclinical models.

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic dataset that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor five-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB patients.

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

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, IL1ß, 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.

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN).

Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC50 profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.

Analysis of differential secondary effects of novel rexinoids: select rexinoid X receptor ligands demonstrate differentiated side effect profiles.

In order to determine the feasibility of utilizing novel rexinoids for chemotherapeutics and as potential treatments for neurological conditions, we undertook an assessment of the side effect profile of select rexinoid X receptor (RXR) analogs that we reported previously. We assessed pharmacokinetic profiles, lipid and thyroid-stimulating hormone (TSH) levels in rats, and cell culture activity of rexinoids in sterol regulatory element-binding protein (SREBP) induction and thyroid hormone inhibition assays. We also performed RNA sequencing of the brain tissues of rats that had been dosed with the compounds. We show here for the first time that potent rexinoid activity can be uncoupled from drastic lipid changes and thyroid axis variations, and we propose that rexinoids can be developed with improved side effect profiles than the parent compound, bexarotene (1).