Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs

被引：68

作者：

Law, Robert P. ^{[1
]}

Nunes, Joao ^{[1
]}

Chung, Chun-wa ^{[1
]}

Bantscheff, Marcus ^{[2
]}

Buda, Karol ^{[1
]}

Dai, Han ^{[1
]}

Evans, John P. ^{[1
]}

Flinders, Adam ^{[1
]}

Klimaszewska, Diana ^{[1
]}

Lewis, Antonia J. ^{[1
]}

Muelbaier, Marcel ^{[2
]}

Scott-Stevens, Paul ^{[1
]}

Stacey, Peter ^{[1
]}

Tame, Christopher J. ^{[1
]}

Watt, Gillian F. ^{[1
]}

Zinn, Nico ^{[2
]}

Queisser, Markus A. ^{[1
]}

Harling, John D. ^{[1
]}

Benowitz, Andrew B. ^{[1
]}

机构：

[1] GlaxoSmithKline, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[2] Cellzome GmbH, Meyerhofstr 1, D-69117 Heidelberg, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2021年 / 60卷 / 43期

关键词：

cancer; drug design; medicinal chemistry; protein degradation; proteolysis-targeting chimeras (PROTACs); FOCAL ADHESION KINASE; GROWTH-FACTOR RECEPTOR-3; PHASE-I; INHIBITOR; APOPTOSIS;

D O I：

10.1002/anie.202109237

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (approximate to 96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.

引用

页码：23327 / 23334

页数：8

共 42 条

[1] [Anonymous], 2021, ANGEW CHEM, V133, P16041
[2] Bondeson DP, 2015, NAT CHEM BIOL, V11, P611, DOI [10.1038/NCHEMBIO.1858, 10.1038/nchembio.1858]
[3] Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery
Burslem, George M.
Crews, Craig M.
[J]. CELL, 2020, 181 (01) : 102 - 114
[4] Disrupting the Scaffold to Improve Focal Adhesion Kinase-Targeted Cancer Therapeutics
Cance, William G.
Kurenova, Elena
Marlowe, Timothy
Golubovskaya, Vita
[J]. SCIENCE SIGNALING, 2013, 6 (268) : pe10
[5] Structural Insights into PROTAC-Mediated Degradation of BcI-xL
Chung, Chun-wa
Dai, Han
Fernandez, Esther
Tinworth, Christopher P.
Churcher, Ian
Cryan, Jenni
Denyer, Jane
Harling, John D.
Konopacka, Agnieszka
Queisser, Markus A.
Tame, Christopher J.
Watt, Gillian
Jiang, Fan
Qian, Dongming
Benowitz, Andrew B.
[J]. ACS CHEMICAL BIOLOGY, 2020, 15 (09) : 2316 - 2323
[6] Crews CM., 2020, Patent No. [2020023851, WO2020023851]
[7] Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation
Cromm, Philipp M.
Samarasinghe, Kusal T. G.
Hines, John
Crews, Craig M.
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2018, 140 (49) : 17019 - 17026
[8] Phase I Study of BI 853520, an Inhibitor of Focal Adhesion Kinase, in Patients with Advanced or Metastatic Nonhematologic Malignancies
de Jonge, Maja J. A.
Steeghs, Neeltje
Lolkema, Martijn P.
Hotte, Sebastien J.
Hirte, Hal W.
van der Biessen, Diane A. J.
Razak, Albiruni R. Abdul
De Vos, Filip Y. F. L.
Verheijen, Remy B.
Schnell, David
Pronk, Linda C.
Jansen, Monique
Siu, Lillian L.
[J]. TARGETED ONCOLOGY, 2019, 14 (01) : 43 - 55
[9] Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2
Du, Guangyan
Jiang, Jie
Wu, Qibiao
Henning, Nathaniel J.
Donovan, Katherine A.
Yue, Hong
Che, Jianwei
Lu, Wenchao
Fischer, Eric S.
Bardeesy, Nabeel
Zhang, Tinghu
Gray, Nathanael S.
[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2021, 60 (29) : 15905 - 15911
[10] Function of Focal Adhesion Kinase Scaffolding to Mediate Endophilin A2 Phosphorylation Promotes Epithelial-Mesenchymal Transition and Mammary Cancer Stem Cell Activities in Vivo
Fan, Huaping
Zhao, Xiaofeng
Sun, Shaogang
Luo, Ming
Guan, Jun-Lin
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (05) : 3322 - 3333

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