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Ethyl 2-((4-Chlorophenyl)amino)thiazole-4-carboxylate and Derivatives Are Potent Inducers of Oct3/4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-07-23 00:00:00 , DOI: 10.1021/acs.jmedchem.5b00226 Xinlai Cheng 1 , Hiroki Yoshida 1 , Dena Raoofi 1 , Sawsan Saleh 1 , Hamed Alborzinia 1 , Frank Wenke 2 , Axel Göhring 2 , Stefanie Reuter 2 , Nancy Mah 3 , Heiko Fuchs 4 , Miguel A. Andrade-Navarro 3 , James Adjaye 4 , Sheraz Gul 5 , Jochen Utikal 6 , Ralf Mrowka 2 , Stefan Wölfl 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-07-23 00:00:00 , DOI: 10.1021/acs.jmedchem.5b00226 Xinlai Cheng 1 , Hiroki Yoshida 1 , Dena Raoofi 1 , Sawsan Saleh 1 , Hamed Alborzinia 1 , Frank Wenke 2 , Axel Göhring 2 , Stefanie Reuter 2 , Nancy Mah 3 , Heiko Fuchs 4 , Miguel A. Andrade-Navarro 3 , James Adjaye 4 , Sheraz Gul 5 , Jochen Utikal 6 , Ralf Mrowka 2 , Stefan Wölfl 1
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The octamer-binding transcription factor 4 (Oct3/4) is a master gene in the transcriptional regulatory network of pluripotent cells. Repression of Oct3/4 in embryonic stem cells (ESCs) is associated with cell differentiation and loss of pluripotency, whereas forced overexpression in cooperation with other transcriptional factors, such as Nanog, Sox2, and Lin28, can reprogram somatic cells back into pluripotent cells, termed induced pluripotent stem cells (iPSCs). However, random integration and potential tumorigenic transformation caused by viral transduction limit the clinical application of iPSCs. By performing a cell-based high throughput screening (HTS) campaign, we identified several potential small molecules as inducers of Oct3/4 expression. Here we report a lead structure ethyl 2-((4-chlorophenyl)amino)-thiazole-4-carboxylate, termed O4I2, showing high activity in enforcing Oct3/4 expression. On the basis of chemical expansion, we further identified derivatives having increased activities toward Oct3/4 induction. Thus, O4I2 and its derivatives should provide a new class of small molecules suitable for iPSC generation.
中文翻译：
2-（（4-氯苯基）氨基）噻唑-4-羧酸乙酯及其衍生物是Oct3 / 4的强诱导剂
八聚物结合转录因子4（Oct3 / 4）是多能细胞转录调控网络中的一个主基因。胚胎干细胞（ESC）中Oct3 / 4的抑制与细胞分化和多能性的丧失相关，而与其他转录因子（如Nanog，Sox2和Lin28）合作而被迫过度表达则可以将体细胞重新编程为多能细胞，称为诱导多能干细胞（iPSC）。然而，由病毒转导引起的随机整合和潜在的致瘤转化限制了iPSC的临床应用。通过执行基于细胞的高通量筛选（HTS）活动，我们确定了几个潜在的小分子作为Oct3 / 4表达的诱导剂。在这里，我们报告了2-（（4-氯苯基）氨基）-噻唑-4-羧酸乙酯的铅结构，称为O4I2，在执行Oct3 / 4表达方面显示出高活性。基于化学膨胀，我们进一步鉴定了对Oct3 / 4诱导具有增加的活性的衍生物。因此，O4I2及其衍生物应提供适用于iPSC产生的一类新的小分子。
更新日期：2015-07-23
中文翻译：
2-（（4-氯苯基）氨基）噻唑-4-羧酸乙酯及其衍生物是Oct3 / 4的强诱导剂
八聚物结合转录因子4（Oct3 / 4）是多能细胞转录调控网络中的一个主基因。胚胎干细胞（ESC）中Oct3 / 4的抑制与细胞分化和多能性的丧失相关，而与其他转录因子（如Nanog，Sox2和Lin28）合作而被迫过度表达则可以将体细胞重新编程为多能细胞，称为诱导多能干细胞（iPSC）。然而，由病毒转导引起的随机整合和潜在的致瘤转化限制了iPSC的临床应用。通过执行基于细胞的高通量筛选（HTS）活动，我们确定了几个潜在的小分子作为Oct3 / 4表达的诱导剂。在这里，我们报告了2-（（4-氯苯基）氨基）-噻唑-4-羧酸乙酯的铅结构，称为O4I2，在执行Oct3 / 4表达方面显示出高活性。基于化学膨胀，我们进一步鉴定了对Oct3 / 4诱导具有增加的活性的衍生物。因此，O4I2及其衍生物应提供适用于iPSC产生的一类新的小分子。
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