HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of Halo Tag Fusion Proteins

被引：315

作者：

Buckley, Dennis L. ^{[1
]}

Raina, Kanak ^{[1
]}

Darricarrere, Nicole ^{[2
]}

Hines, John ^{[2
]}

Gustafson, Jeffrey L. ^{[1
]}

Smith, Ian E. ^{[4
]}

Miah, Aija H. ^{[4
]}

Harling, John D. ^{[4
]}

Crews, Craig M. ^{[1
,2
,3
]}

机构：

[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA

[2] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA

[3] Yale Univ, Dept Pharmacol, New Haven, CT 06520 USA

[4] GlaxoSmithKline, Prot Degradat Discovery Performance Unit, Stevenage SG1 2NY, Herts, England

来源：

ACS CHEMICAL BIOLOGY | 2015年 / 10卷 / 08期

基金：

美国国家卫生研究院;

关键词：

TARGETED DEGRADATION; PROTEASOME INHIBITOR; LIVING CELLS; CANCER; UBIQUITINATION; ACTIVATION; KNOCKDOWN; TOOL; ANTAGONISTS; EPOXOMICIN;

D O I：

10.1021/acschembio.5b00442

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method for inducing targeted protein degradation involves the use of PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired protein of interest. PROTACs have been successfully used to degrade numerous proteins in cells, but the peptidic E3 ligase ligands used in previous PROTACs have hindered their development into more mature chemical probes or therapeutics. We report the design of a novel class of PROTACs that incorporate small molecule VHL ligands to successfully degrade HaloTag7 fusion proteins. These HaloPROTACs will inspire the development of future PROTACs with more drug-like properties. Additionally, these HaloPROTACs are useful chemical genetic tools, due to their ability to chemically knock down widely used HaloTag7 fusion proteins in a general fashion.

引用

页码：1831 / 1837

页数：7

共 39 条

[31] Chemical genetic control of protein levels: Selective in vivo targeted degradation
Schneekloth, JS
Fonseca, FN
Koldobskiy, M
Mandal, A
Deshaies, R
Sakamoto, K
Crews, CM
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126 (12) : 3748 - 3754
[32] Broadly Applicable Methodology for the Rapid and Dosable Small Molecule-Mediated Regulation of Transcription Factors in Human Cells
Shoulders, Matthew D.
Ryno, Lisa M.
Cooley, Christina B.
Kelly, Jeffery W.
Wiseman, R. Luke
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2013, 135 (22) : 8129 - 8132
[33] Stress-Independent Activation of XBP1s and/or ATF6 Reveals Three Functionally Diverse ER Proteostasis Environments
Shoulders, Matthew D.
Ryno, Lisa M.
Genereux, Joseph C.
Moresco, James J.
Tu, Patricia G.
Wu, Chunlei
Yates, John R., III
Su, Andrew I.
Kelly, Jeffery W.
Wiseman, R. Luke
[J]. CELL REPORTS, 2013, 3 (04): : 1279 - 1292
[34] Total synthesis of the potent proteasome inhibitor epoxomicin: A useful tool for understanding proteasome biology
Sin, N
Kim, KB
Elofsson, M
Meng, LH
Auth, H
Kwok, BHB
Crews, CM
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (15) : 2283 - 2288
[35] Identification of Hydrophobic Tags for the Degradation of Stabilized Proteins
Tae, Hyun Seop
Sundberg, Thomas B.
Neklesa, Taavi K.
Noblin, Devin J.
Gustafson, Jeffrey L.
Roth, Anke G.
Raina, Kanak
Crews, Craig M.
[J]. CHEMBIOCHEM, 2012, 13 (04) : 538 - 541
[36] BESTATIN, AN INHIBITOR OF AMINOPEPTIDASE-B, PRODUCED BY ACTINOMYCETES
UMEZAWA, H
AOYAGI, T
SUDA, H
HAMADA, M
TAKEUCHI, T
[J]. JOURNAL OF ANTIBIOTICS, 1976, 29 (01) : 97 - 99
[37] Dissecting Fragment-Based Lead Discovery at the von Hippel-Lindau Protein:Hypoxia Inducible Factor 1α Protein-Protein Interface
Van Molle, Inge
Thomann, Andreas
Buckley, Dennis L.
So, Ernest C.
Lang, Steffen
Crews, Craig M.
Ciulli, Alessio
[J]. CHEMISTRY & BIOLOGY, 2012, 19 (10): : 1300 - 1312
[38] IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis
Varfolomeev, Eugene
Blankenship, John W.
Wayson, Sarah M.
Fedorova, Anna V.
Kayagaki, Nobuhiko
Garg, Parie
Zobel, Kerry
Dynek, Jasmin N.
Elliott, Linda O.
Wallweber, Heidi J. A.
Flygare, John A.
Fairbrother, Wayne J.
Deshayes, Kurt
Dixit, Vishva M.
Vucic, Domagoj
[J]. CELL, 2007, 131 (04) : 669 - 681
[39] In vivo activation of the p53 pathway by small-molecule antagonists of MDM2
Vassilev, LT
Vu, BT
Graves, B
Carvajal, D
Podlaski, F
Filipovic, Z
Kong, N
Kammlott, U
Lukacs, C
Klein, C
Fotouhi, N
Liu, EA
[J]. SCIENCE, 2004, 303 (5659) : 844 - 848

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