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From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-10-22 , DOI: 10.1016/j.chembiol.2019.10.002 Whitney L Petrilli 1 , Gregory C Adam 2 , Roman S Erdmann 3 , Pravien Abeywickrema 4 , Vijayalakshmi Agnani 5 , Xi Ai 6 , Jen Baysarowich 5 , Noel Byrne 4 , John P Caldwell 1 , Wonsuk Chang 1 , Edward DiNunzio 5 , Zhe Feng 1 , Rachael Ford 4 , Sookhee Ha 7 , Yongcheng Huang 6 , Brian Hubbard 6 , Jennifer M Johnston 4 , Michael Kavana 5 , Jean-Marie Lisnock 5 , Rui Liang 1 , Jun Lu 4 , Zhijian Lu 1 , Juncai Meng 4 , Peter Orth 7 , Oksana Palyha 6 , Gopal Parthasarathy 4 , Scott P Salowe 5 , Sujata Sharma 4 , Jennifer Shipman 4 , Stephen M Soisson 4 , Alison M Strack 6 , Hyewon Youm 1 , Kake Zhao 1 , Deborah L Zink 5 , Hratch Zokian 5 , George H Addona 5 , Karen Akinsanya 6 , James R Tata 1 , Yusheng Xiong 1 , Jason E Imbriglio 1
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-10-22 , DOI: 10.1016/j.chembiol.2019.10.002 Whitney L Petrilli 1 , Gregory C Adam 2 , Roman S Erdmann 3 , Pravien Abeywickrema 4 , Vijayalakshmi Agnani 5 , Xi Ai 6 , Jen Baysarowich 5 , Noel Byrne 4 , John P Caldwell 1 , Wonsuk Chang 1 , Edward DiNunzio 5 , Zhe Feng 1 , Rachael Ford 4 , Sookhee Ha 7 , Yongcheng Huang 6 , Brian Hubbard 6 , Jennifer M Johnston 4 , Michael Kavana 5 , Jean-Marie Lisnock 5 , Rui Liang 1 , Jun Lu 4 , Zhijian Lu 1 , Juncai Meng 4 , Peter Orth 7 , Oksana Palyha 6 , Gopal Parthasarathy 4 , Scott P Salowe 5 , Sujata Sharma 4 , Jennifer Shipman 4 , Stephen M Soisson 4 , Alison M Strack 6 , Hyewon Youm 1 , Kake Zhao 1 , Deborah L Zink 5 , Hratch Zokian 5 , George H Addona 5 , Karen Akinsanya 6 , James R Tata 1 , Yusheng Xiong 1 , Jason E Imbriglio 1
Affiliation
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Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.
中文翻译：
从筛选到目标降解：发现和优化PCSK9小分子配体的策略。
前蛋白转化酶类促肾上腺素样/ kexin型9（PCSK9）是一种丝氨酸蛋白酶，参与蛋白质与低密度脂蛋白（LDL）受体的相互作用，具有人类遗传和临床验证。阻止这种蛋白质-蛋白质相互作用可防止LDL受体降解，从而降低LDL胆固醇水平。我们针对这种难以药物化的PPI目标的小分子直接结合剂的追求利用了亲和力选择/质谱法，该方法鉴定了一种已确认的命中化合物。X射线晶体结构表明该化合物结合在位于催化和C-末端结构域之间的空前的变构口袋中。使用两种截然不同的策略对这一初始命中值进行优化，可得到对PCSK9具有高结合亲和力的化合物。通过细胞热位移测定法证明了细胞裂解物中的直接靶标参与。最后，用蛋白酶体募集标签显示了配体诱导的蛋白质降解，该标签附着在PCSK9的高亲和力变构配体上。
更新日期：2019-11-09
中文翻译：
从筛选到目标降解：发现和优化PCSK9小分子配体的策略。
前蛋白转化酶类促肾上腺素样/ kexin型9（PCSK9）是一种丝氨酸蛋白酶，参与蛋白质与低密度脂蛋白（LDL）受体的相互作用，具有人类遗传和临床验证。阻止这种蛋白质-蛋白质相互作用可防止LDL受体降解，从而降低LDL胆固醇水平。我们针对这种难以药物化的PPI目标的小分子直接结合剂的追求利用了亲和力选择/质谱法，该方法鉴定了一种已确认的命中化合物。X射线晶体结构表明该化合物结合在位于催化和C-末端结构域之间的空前的变构口袋中。使用两种截然不同的策略对这一初始命中值进行优化，可得到对PCSK9具有高结合亲和力的化合物。通过细胞热位移测定法证明了细胞裂解物中的直接靶标参与。最后，用蛋白酶体募集标签显示了配体诱导的蛋白质降解，该标签附着在PCSK9的高亲和力变构配体上。
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