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Analysis of Retinoid X Receptor (RXR) Homodimerization Driven by RXR Ligands Using Yeast Two-Hybrid

Description

Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors

Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor and in return control cell differentiation and proliferation. Bexarotene targets RXR homodimerization to drive transcription of tumor suppressing genes; however, adverse reactions occur simultaneously when bound to other nuclear receptors. In this study, we used novel bexarotene analogs throughout 5 iterations synthesized in the laboratory of Dr. Wagner to test for their potency and ability to bind RXR. The aim of our study is to quantitatively measure RXR homodimerization driven by bexarotene analogs using a yeast two-hybrid system. Our results suggests there to be several compounds with higher protein activity than bexarotene, particularly in generations 3.0 and 5.0. This higher affinity for RXR homodimers may help scientists identify a compound that will minimize adverse effects and toxicity of bexarotene and serve as a better cancer treatment alternative.

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Date Created
2015-05

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Characterization of Second and Third Generation, Novel RXR Selction Agonists for the Treatment of Cutaneous T-Cell Lymphoma

Description

Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost

Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.

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Date Created
2012-05

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Synthesis of Novel Rexinoids for Use in Preclinical Trials of Cancer Models

Description

Rexinoids such as Bexarotene have been developed as effective treatments of different diseases including lymphoma, breast cancer, lung cancer, Alzheimer’s disease, and diabetes. This is due to the widespread nature of the retinoid X receptor, which is the target of

Rexinoids such as Bexarotene have been developed as effective treatments of different diseases including lymphoma, breast cancer, lung cancer, Alzheimer’s disease, and diabetes. This is due to the widespread nature of the retinoid X receptor, which is the target of these drugs, throughout the body. However, Bexarotene is not infallible and has many negative side effects which limit the use of the drug to only a short period of time. This may be fine for chemotherapy, but rexinoids have been proposed to also be effective at preventing cancer as well. This is not currently possible with the side effects seen with approved rexinoids. Due to this, six novel rexinoids were created in hopes of reducing the side effect profile of rexinoids. The idea of dual agonism was also explored with two of the compounds created as well. All six of these compounds, after creation and purification, were sent off for in vitro and in vivo testing to confirm side effect profile and efficacy.

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2020-05