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Translation Termination Factor GSPT1 Is a Phenotypically Relevant Off-Target of Heterobifunctional Phthalimide Degraders
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-01-22 00:00:00 , DOI: 10.1021/acschembio.7b00969 Mette Ishoey 1 , Someth Chorn 2 , Natesh Singh 3 , Martin G. Jaeger 2 , Matthias Brand 2 , Joshiawa Paulk 1, 4 , Sophie Bauer 2 , Michael A. Erb 1 , Katja Parapatics 2 , André C. Müller 2 , Keiryn L. Bennett 2 , Gerhard F. Ecker 3 , James E. Bradner 1, 4 , Georg E. Winter 2
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-01-22 00:00:00 , DOI: 10.1021/acschembio.7b00969 Mette Ishoey 1 , Someth Chorn 2 , Natesh Singh 3 , Martin G. Jaeger 2 , Matthias Brand 2 , Joshiawa Paulk 1, 4 , Sophie Bauer 2 , Michael A. Erb 1 , Katja Parapatics 2 , André C. Müller 2 , Keiryn L. Bennett 2 , Gerhard F. Ecker 3 , James E. Bradner 1, 4 , Georg E. Winter 2
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Protein degradation is an emerging therapeutic strategy with a unique molecular pharmacology that enables the disruption of all functions associated with a target. This is particularly relevant for proteins depending on molecular scaffolding, such as transcription factors or receptor tyrosine kinases (RTKs). To address tractability of multiple RTKs for chemical degradation by the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN), we synthesized a series of phthalimide degraders based on the promiscuous kinase inhibitors sunitinib and PHA665752. While both series failed to induce degradation of their consensus targets, individual molecules displayed pronounced efficacy in leukemia cell lines. Orthogonal target identification supported by molecular docking led us to identify the translation termination factor G1 to S phase transition 1 (GSPT1) as a converging off-target, resulting from inadvertent E3 ligase modulation. This research highlights the importance of monitoring degradation events that are independent of the respective targeting ligand as a unique feature of small-molecule degraders.
中文翻译：
翻译终止因子GSPT1是异双功能邻苯二甲酰亚胺降解物的表型相关脱靶。
蛋白质降解是一种新兴的治疗策略，具有独特的分子药理作用，能够破坏与靶标相关的所有功能。这对于取决于分子支架的蛋白质（例如转录因子或受体酪氨酸激酶（RTK））尤其重要。解决通过E3连接酶CUL4-RBX1-DDB1-CRBN（CRL4 CRBN）进行化学降解的多个RTK的易处理性），我们基于混杂的激酶抑制剂sunitinib和PHA665752合成了一系列邻苯二甲酰亚胺降解剂。虽然两个系列均未能诱导其共有靶标的降解，但单个分子在白血病细胞系中显示出明显的功效。分子对接支持的正交靶标识别使我们能够将翻译终止因子G1到S相变1（GSPT1）识别为由于无意中E3连接酶调节而导致的趋同脱靶。这项研究强调了监测降解事件的重要性，该事件独立于各个靶向配体，是小分子降解剂的独特功能。
更新日期：2018-01-22
中文翻译：
翻译终止因子GSPT1是异双功能邻苯二甲酰亚胺降解物的表型相关脱靶。
蛋白质降解是一种新兴的治疗策略，具有独特的分子药理作用，能够破坏与靶标相关的所有功能。这对于取决于分子支架的蛋白质（例如转录因子或受体酪氨酸激酶（RTK））尤其重要。解决通过E3连接酶CUL4-RBX1-DDB1-CRBN（CRL4 CRBN）进行化学降解的多个RTK的易处理性），我们基于混杂的激酶抑制剂sunitinib和PHA665752合成了一系列邻苯二甲酰亚胺降解剂。虽然两个系列均未能诱导其共有靶标的降解，但单个分子在白血病细胞系中显示出明显的功效。分子对接支持的正交靶标识别使我们能够将翻译终止因子G1到S相变1（GSPT1）识别为由于无意中E3连接酶调节而导致的趋同脱靶。这项研究强调了监测降解事件的重要性，该事件独立于各个靶向配体，是小分子降解剂的独特功能。
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