公开(公告)号：US20180215731A1

公开(公告)日：2018-08-02

申请号：US15885671

申请日：2018-01-31

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Michael Berlin ,  Hanqing Dong ,  Keith R. Homberger ,  Yimin Qian ,  Lawrence B. Snyder ,  Jing Wang ,  Kurt Zimmermann

IPC分类号： C07D401/14 ,  C07D417/14 ,  C07D471/04 ,  C07D471/10 ,  C07D487/04 ,  C07D495/14 ,  C07D498/04 ,  A61P35/02

CPC分类号： C07D401/14 ,  A61P35/02 ,  C07D417/14 ,  C07D471/04 ,  C07D471/10 ,  C07D487/04 ,  C07D495/14 ,  C07D498/04

摘要： The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

公开(公告)号：US20180072711A1

公开(公告)日：2018-03-15

申请号：US15706064

申请日：2017-09-15

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Yimin Qian ,  Hanqing Dong ,  Jing Wang ,  Craig M. Crews

IPC分类号： C07D417/14 ,  C07D413/14 ,  C07D403/14 ,  C07D403/12

CPC分类号： C07D417/14 ,  C07D403/12 ,  C07D403/14 ,  C07D413/14 ,  C07K5/06034 ,  C07K5/06052

摘要： The present disclosure relates to compounds and a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing the compounds, and processes for their preparation. The disclosure also relates to the use of the compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor.

公开(公告)号：US20170281784A1

公开(公告)日：2017-10-05

申请号：US15477966

申请日：2017-04-03

申请人： Arvinas, Inc.

发明人： Jing Wang ,  Andrew P. Crew ,  Hanqing Dong ,  Taavi Neklesa ,  Brian Hamman

IPC分类号： A61K47/48 ,  G06F19/18 ,  G06F19/16 ,  A61K31/277 ,  C40B30/04 ,  A61K31/551 ,  A61K31/4166 ,  G01N33/68 ,  A61K38/05

CPC分类号： A61K31/277 ,  A61K31/4166 ,  A61K31/551 ,  A61K38/05 ,  A61K47/55 ,  G01N33/6845 ,  G16B15/00 ,  G16B20/00 ,  G16C20/50

摘要： The present disclosure is based on the surprising and unexpected discovery that a ligand molecule with certain characteristics is able to bind to two protein molecules simultaneously and recruit them to form a transient or stable protein-protein interaction complex. The protein-protein interaction and other cross-domain interactions gained in this process contribute additional stabilization energy to the complex beyond the combination of the binary binding energies, and therefore, largely increase the binding potency of the ligand. Accordingly, the present disclosure provides a Protein-Protein Interaction Inducing Technology (PPIIT), which includes a method to design and identify the tripartite or bifunctional compounds and use such compounds to induce protein-protein interactions in various contexts. The present disclosure also provides a composition for the purpose of inducing protein-protein interactions.

公开(公告)号：US20160214972A1

公开(公告)日：2016-07-28

申请号：US15002303

申请日：2016-01-20

申请人： Arvinas, Inc.

发明人： Meizhong Jin ,  Andrew P. Crew ,  Hanqing Dong ,  Jing Wang ,  Kam Siu ,  Caterina Ferraro ,  Xin Chen ,  Yimin Qian

IPC分类号： C07D417/14 ,  C07D413/14 ,  A61K31/422 ,  A61K31/4439 ,  C07D417/12 ,  A61K45/06 ,  A61K31/4545 ,  C07D233/86 ,  C07D401/04 ,  C07D491/107 ,  C07D471/10 ,  A61K31/427 ,  C07D413/12

CPC分类号： C07D417/14 ,  A61K45/06 ,  A61P25/28 ,  A61P35/00 ,  C07D233/86 ,  C07D401/04 ,  C07D413/12 ,  C07D413/14 ,  C07D417/12 ,  C07D471/10 ,  C07D491/107 ,  C07K5/06165

摘要： The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of Androgen Receptor.

摘要翻译： 本发明涉及双功能化合物，其可用于降解和（抑制）雄激素受体。 特别地，本发明涉及一种化合物，其一端含有与泛素连接酶结合的VHL配体，另一端含有结合雄激素受体的部分，使得雄激素受体置于接近泛素连接酶的作用下 降解（和抑制）雄激素受体。 与根据本发明的化合物相关的与雄激素受体的降解/抑制一致的本发明显示出广泛的药理学活性。

公开(公告)号：US20160058872A1

公开(公告)日：2016-03-03

申请号：US14792414

申请日：2015-07-06

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Craig Crews ,  Hanqing Dong ,  Jing Wang ,  Yimin Qian ,  Kam Siu ,  Meizhong Jin

IPC分类号： A61K47/48 ,  C07D495/14 ,  C07D417/14 ,  A61K31/426 ,  A61K31/505 ,  A61K31/454 ,  A61K31/551 ,  C07D401/14 ,  A61K45/06

CPC分类号： A61K31/426 ,  A61K31/454 ,  A61K31/505 ,  A61K31/551 ,  A61K45/06 ,  A61K47/545 ,  A61K47/555 ,  A61K47/66 ,  C07D401/04 ,  C07D401/14 ,  C07D409/14 ,  C07D417/14 ,  C07D487/04 ,  C07D495/14 ,  C07D498/14 ,  C07K14/4705 ,  C07K14/721 ,  C12N9/12 ,  C12N9/18 ,  C12Q1/25 ,  C12Y207/11001 ,  C12Y301/01031 ,  G01N2333/9015 ,  G01N2500/02

摘要： The description relates to imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

公开(公告)号：US11352351B2

公开(公告)日：2022-06-07

申请号：US15002303

申请日：2016-01-20

申请人： Arvinas, Inc.

发明人： Meizhong Jin ,  Andrew P. Crew ,  Hanqing Dong ,  Jing Wang ,  Xin Chen ,  Yimin Qian

IPC分类号： C07D417/14 ,  C07D413/14 ,  A61K31/422 ,  A61K31/4439 ,  C07D417/12 ,  A61K45/06 ,  A61K31/4545 ,  C07D233/86 ,  C07D401/04 ,  C07D491/107 ,  C07D471/10 ,  A61K31/427 ,  C07D413/12 ,  C07K5/078 ,  A61P35/00 ,  A61P25/28

摘要： The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of Androgen Receptor.

公开(公告)号：US20180346461A1

公开(公告)日：2018-12-06

申请号：US16048191

申请日：2018-07-27

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Hanqing Dong ,  Jing Wang ,  Xin Chen ,  Yimin Qian ,  Kurt Zimmermann ,  Craig M. Crews ,  Michael Berlin ,  Lawrence Snyder

IPC分类号： C07D417/14 ,  A61P25/28 ,  A61P35/00 ,  C07K5/078 ,  C07D413/14 ,  C07D417/12 ,  C07D471/10 ,  C07D491/107 ,  C07D401/04 ,  C07D233/86 ,  C07D413/12 ,  A61K45/06

CPC分类号： C07D417/14 ,  A61K45/06 ,  A61P25/28 ,  A61P35/00 ,  C07D233/86 ,  C07D401/04 ,  C07D413/12 ,  C07D413/14 ,  C07D417/12 ,  C07D471/10 ,  C07D491/107 ,  C07K5/06165

摘要： The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of Androgen Receptor.

公开(公告)号：US10071164B2

公开(公告)日：2018-09-11

申请号：US14822309

申请日：2015-08-10

申请人： Yale University ,  Arvinas, Inc.

发明人： Andrew Crew ,  Craig Crews ,  Hanqing Dong ,  Eunhwa Ko ,  Jing Wang

IPC分类号： C07K5/062 ,  C07K5/097 ,  A61K45/06 ,  A61K31/427 ,  A61K31/426 ,  A61K38/00 ,  A61K47/48

CPC分类号： A61K47/55 ,  A61K31/426 ,  A61K31/427 ,  A61K38/00 ,  A61K45/06 ,  A61K47/545 ,  A61K47/551 ,  C07K5/06026 ,  C07K5/06034 ,  C07K5/06052 ,  C07K5/0821

摘要： The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

公开(公告)号：US20180179183A1

公开(公告)日：2018-06-28

申请号：US15853166

申请日：2017-12-22

申请人： Arvinas, Inc. ,  Yale University

发明人： Andrew P. Crew ,  Keith R. Hornberger ,  Jing Wang ,  Hanqing Dong ,  Yimin Qian ,  Craig M. Crews ,  Saul Jaime-Figueroa

IPC分类号： C07D401/14 ,  C07D401/04 ,  A61K31/4439 ,  C07D417/14 ,  A61K31/4545 ,  C07D487/04 ,  A61K31/4188 ,  C07D471/04 ,  A61K31/437 ,  A61K45/06 ,  A61P35/00 ,  A61P43/00 ,  A61P25/00 ,  A61P9/00

摘要： The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

公开(公告)号：US20170065719A1

公开(公告)日：2017-03-09

申请号：US15230354

申请日：2016-08-05

申请人： Arvinas, Inc. ,  Yale University

发明人： Yimin Qian ,  Hanqing Dong ,  Jing Wang ,  Michael Berlin ,  Andrew P. Crew ,  Craig M. Crews

IPC分类号： A61K47/48 ,  A61K45/06 ,  A61K31/422 ,  A61K31/437 ,  A61K31/551 ,  A61K31/427

摘要： The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

摘要翻译： 本发明涉及双官能化合物，其可用作靶向泛素化的调节剂，特别是根据本发明的双官能化合物降解和/或以其它方式抑制的多种多肽和其它蛋白质的抑制剂。 特别地，本发明涉及化合物，其一端含有与泛素连接酶结合的VHL配体，另一端含有结合靶蛋白的部分，使得靶蛋白置于接近泛素连接酶 以实现该蛋白质的降解（和抑制）。 与靶向多肽的降解/抑制一致，本发明表现出与根据本发明的化合物相关的广泛的药理学活性。