An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene
Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene...
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2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| author | Peter W. Jurutka Orsola di Martino Sabeeha Reshi Sanchita Mallick Michael A. Sausedo Grant A. Moen Isaac J. Lee Dominic J. Ivan Tyler D. Krall Samuel J. Peoples Anthony Perez Lucas Tromba Anh Le Iraj Khadka Ryan Petros Brianna M. Savage Eleine Salama Jakline Salama Joseph W. Ziller Youngbin Noh Ming-Yue Lee Wei Liu John S. Welch Pamela A. Marshall Carl E. Wagner |
| author_facet | Peter W. Jurutka Orsola di Martino Sabeeha Reshi Sanchita Mallick Michael A. Sausedo Grant A. Moen Isaac J. Lee Dominic J. Ivan Tyler D. Krall Samuel J. Peoples Anthony Perez Lucas Tromba Anh Le Iraj Khadka Ryan Petros Brianna M. Savage Eleine Salama Jakline Salama Joseph W. Ziller Youngbin Noh Ming-Yue Lee Wei Liu John S. Welch Pamela A. Marshall Carl E. Wagner |
| author_sort | Peter W. Jurutka |
| collection | DOAJ |
| description | Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (<b>1</b>). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC<sub>50</sub> as well as IC<sub>50</sub> values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than <b>1</b>. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to <b>1</b>. |
| first_indexed | 2024-03-09T16:18:34Z |
| format | Article |
| id | doaj.art-27eb2a9c59ad425590465f2845109e80 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:18:34Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-27eb2a9c59ad425590465f2845109e802023-11-24T15:34:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123241621310.3390/ijms232416213An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than BexarotenePeter W. Jurutka0Orsola di Martino1Sabeeha Reshi2Sanchita Mallick3Michael A. Sausedo4Grant A. Moen5Isaac J. Lee6Dominic J. Ivan7Tyler D. Krall8Samuel J. Peoples9Anthony Perez10Lucas Tromba11Anh Le12Iraj Khadka13Ryan Petros14Brianna M. Savage15Eleine Salama16Jakline Salama17Joseph W. Ziller18Youngbin Noh19Ming-Yue Lee20Wei Liu21John S. Welch22Pamela A. Marshall23Carl E. Wagner24School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USADepartment of Internal Medicine, Washington University, St. Louis, MO 63110, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USADepartment of Chemistry, University of California, Irvine, CA 92697, USASchool of Molecular Sciences, Arizona State University, Tempe, AZ 85281, USAPoseida Therapeutics, Inc. 9390 Towne Centre Drive, Suite 200, San Diego, CA 92121, USACancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USAA2 Biotherapeutics, 30301 Agoura Rd, Agoura Hills, CA 91301, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USASchool of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USABexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (<b>1</b>). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC<sub>50</sub> as well as IC<sub>50</sub> values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than <b>1</b>. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to <b>1</b>.https://www.mdpi.com/1422-0067/23/24/16213retinoid-x-receptorretinoidrexinoidleukemiasmall molecule therapeuticstructure-activity-relationship |
| spellingShingle | Peter W. Jurutka Orsola di Martino Sabeeha Reshi Sanchita Mallick Michael A. Sausedo Grant A. Moen Isaac J. Lee Dominic J. Ivan Tyler D. Krall Samuel J. Peoples Anthony Perez Lucas Tromba Anh Le Iraj Khadka Ryan Petros Brianna M. Savage Eleine Salama Jakline Salama Joseph W. Ziller Youngbin Noh Ming-Yue Lee Wei Liu John S. Welch Pamela A. Marshall Carl E. Wagner An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene International Journal of Molecular Sciences retinoid-x-receptor retinoid rexinoid leukemia small molecule therapeutic structure-activity-relationship |
| title | An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene |
| title_full | An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene |
| title_fullStr | An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene |
| title_full_unstemmed | An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene |
| title_short | An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene |
| title_sort | isochroman analog of cd3254 and allyl isochroman analogs of net tmn prove to be more potent retinoid x receptor rxr selective agonists than bexarotene |
| topic | retinoid-x-receptor retinoid rexinoid leukemia small molecule therapeutic structure-activity-relationship |
| url | https://www.mdpi.com/1422-0067/23/24/16213 |
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