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.
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.
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DOI：
10.3390/ijms232416213
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发表时间：
2022-12-19
影响因子：
5.6
通讯作者：
Wagner, Carl E.
中科院分区：
文献类型：
--
作者：
Jurutka, Peter W.;di Martino, Orsola;Reshi, Sabeeha;Mallick, Sanchita;Sausedo, Michael A.;Moen, Grant A.;Lee, Isaac J.;Ivan, Dominic J.;Krall, Tyler D.;Peoples, Samuel J.;Perez, Anthony;Tromba, Lucas;Le, Anh;Khadka, Iraj;Petros, Ryan;Savage, Brianna M.;Salama, Eleine;Salama, Jakline;Ziller, Joseph W.;Noh, Youngbin;Lee, Ming-Yue;Liu, Wei;Welch, John S.;Marshall, Pamela A.;Wagner, Carl E.
关键词：
贝沙罗汀是FDA批准的用于治疗皮肤T细胞淋巴瘤（CTCL）的药物;然而，其使用会引起或破坏其他类维生素A-X-受体（RXR）依赖性核受体途径，从而引发副作用，包括甲状腺功能减退和甘油三酯升高。合成了两种新的贝沙罗汀类似物，以及三种独特的CD 3254类似物和十三种新的NEt-TMN类似物，并表征了与贝沙罗汀相比它们诱导RXR激动作用的能力（1）。所有三个组中的几个类似物具有异色满环取代贝沙罗汀脂肪族基团。模拟类似物的RXR结合亲和力，并确定KMT 2A-MLLT 3白血病细胞系中所有类似物的EC 50和IC 50值。在LXRE系统中评估所有类似物的肝脏X受体（LXR）活性，以评估化合物通过增加LXR活性引起甘油三酯升高的潜力，以及驱动LXRE介导的脑ApoE表达的转录作为神经退行性疾病中潜在治疗用途的标志物的潜力。初步结果表明，这些化合物显示出广泛的脱靶活性。然而，许多新化合物被观察到比1更有效。虽然一些RXR激动剂交叉信号视黄酸受体（RAR），许多rexinoids在这项工作中显示减少RAR活性。异苯并二氢吡喃基团本身似乎没有显著降低RXR活性。这项研究的结果表明，与1相比，修饰有效的选择性rexinoids如贝沙罗汀，CD 3254和NEt-TMN可以为rexinoids提供增加的RXR选择性，降低的交叉信号传导潜力，以及改善的白血病模型中的抗增殖特性。
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 (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 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 1. 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 1.
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影响因子：
2.7
作者：
Fujii, Shuji;Ohsawa, Fuminori;Kakuta, Hiroki
通讯作者：
Kakuta, Hiroki
影响因子：
7.3
作者：
Jurutka, Peter W.;Kaneko, Ichiro;Wagner, Carl E.
通讯作者：
Wagner, Carl E.
影响因子：
7.3
作者：
Atigadda, VR;Vines, KK;Muccio, DD
通讯作者：
Muccio, DD
DOI：
10.1126/science.1217697
发表时间：
2012-03-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cramer PE;Cirrito JR;Wesson DW;Lee CY;Karlo JC;Zinn AE;Casali BT;Restivo JL;Goebel WD;James MJ;Brunden KR;Wilson DA;Landreth GE
通讯作者：
Landreth GE
影响因子：
3.6
作者：
Faul, MM;Ratz, AM;Winneroski, LL
通讯作者：
Winneroski, LL