Induced Protein Degradation (PROTACs)

Controlling Intracellular Protein Levels using Small Molecules

Less than 20% of the proteome has an enzymatic activity. However, current drug development efforts rely heavily on the identification of enzymatic inhibitors, thus ignoring a significant fraction of the proteome. While RNAi technology theoretically has the potential to address this undruggable proteome, its clinical development has proven challenging.

Our lab is developing different methodologies to address this unmet need. Specifically, we are interested in affecting different intracellular processes via the small molecule control of protein levels. These approaches include the development of new proteasome inhibitors and new methodologies to induce Targeted Protein Degradation. Proteolysis Targeting Chimeras (PROTACs) recruit E3 ubiquitin ligases to targeted proteins, thus hijacking the intracellular protein quality control machinery to induce selective target protein degradation.

By pharmaceutically controlling protein function via novel mechanisms that do not rely upon enzymatic inhibition, these approaches may allow one to target those proteins that are currently not 'pharmacologically vulnerable'.

Crews Lab PROTACs timeline

Relevant Publications

Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase.
Smith BE, Wang SL, Jaime-Figueroa S, Harbin A, Wang J, Hamman BD, Crews CM
Nat Commun. 2019;10(1):131. Published 2019 Jan 10. doi:10.1038/s41467-018-08027-7.

Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation.
Cromm PM, Samarasinghe KTG, Hines J, Crews CM
J Am Chem Soc. 2018 Dec 12;140(49):17019-17026. doi: 10.1021/jacs.8b08008. Epub 2018 Nov 28.

Enhancing Antiproliferative Activity and Selectivity of a FLT-3 Inhibitor by Proteolysis Targeting Chimera Conversion.
Burslem GM, Song J, Chen X, Hines J, Crews CM
J Am Chem Soc. 2018 Dec 5;140(48):16428-16432. doi: 10.1021/jacs.8b10320. Epub 2018 Nov 19.

MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53.
Hines J, Lartigue S, Dong H, Qian Y, Crews CM
Cancer Res. 2019 Jan 1;79(1):251-262. doi: 10.1158/0008-5472.CAN-18-2918. Epub 2018 Nov 1.

Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance.
Salami J, Alabi S, Willard RR, Vitale NJ, Wang J, Dong H, Jin M, McDonnell DP, Crew AP, Neklesa TK, Crews CM
Commun Biol. 2018 Aug 2;1:100. doi: 10.1038/s42003-018-0105-8. eCollection 2018.

Targeting the C481S Ibrutinib-Resistance Mutation in Bruton’s Tyrosine Kinase Using PROTAC-Mediated Degradation.
Buhimschi AD, Armstrong HA, Toure M, Jaime-Figueroa S, Chen TL, Lehman AM, Woyach JA, Johnson AJ, Byrd JC, Crews CM
Biochemistry. 2018 Jul 3;57(26):3564-3575. doi: 10.1021/acs.biochem.8b00391. Epub 2018 Jun 14.

Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead.
Bondeson DP, Smith BE, Burslem GM, Buhimschi AD, Hines J, Jaime-Figueroa S, Wang J, Hamman BD, Ishchenko A, Crews CM
Cell Chem Biol. 2017 Nov 9. pii: S2451-9456(17)30354-9. doi: 10.1016/j.chembiol.2017.09.010.

The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study.
Burslem GM, Smith BE, Lai AC, Jaime-Figueroa S, McQuaid DC, Bondeson DP, Toure M, Dong H, Qian Y, Wang J, Crew AP, Hines J, Crews CM
2017 Oct 25. pii: S2451-9456(17)30353-7. doi: 10.1016/j.chembiol.2017.09.009.

Assessing Different E3 Ligases for Small Molecule Induced Protein Ubiquitination and Degradation.
Ottis P, Toure M, Cromm PM, Ko E, Gustafson JL, Crews CM
ACS Chem Biol. 2017

Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1.
Crew AP, Raina K, Dong H, Qian Y, Wang J, Vigil D, Serebrenik YV, Hamman BD, Morgan A, Ferraro C, Siu K, Neklesa TK, Winkler JD, Coleman KG, Crews CM
J Med Chem. 2017

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.
Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM, Wang J, Chen X, Dong H, Siu K, Winkler JD, Crew AP, Crews CM, Coleman KG.
Proc Natl Acad Sci U S A. 2016 113(26):7124-9.

Small-Molecule PROTACS: New Approaches to Protein Degradation.
Toure M, Crews CM
Angew Chem Int Ed Engl. 2016 55(6):1966-73.

Induced protein degradation: an emerging drug discovery paradigm.
Lai AC, Crews CM
Nat Rev Drug Discov. 2017 16(2):101-114.

Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL.
Lai AC, Toure M, Hellerschmied D, Salami J, Jaime-Figueroa S, Ko E, Hines J, Crews CM
Angew Chem Int Ed Engl. 2016 55(2):807-10.

HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins.
Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL, Smith IE, Miah AH, Harling JD, Crews CM
ACS Chem Biol. 2015 10(8):1831-7

Catalytic in vivo protein knockdown by small-molecule PROTACs.
Bondeson DP, Mares A, Smith IE, Ko E, Campos S, Miah AH, Mulholland KE, Routly N, Buckley DL, Gustafson JL, Zinn N, Grandi P, Shimamura S, Bergamini G, Faelth-Savitski M, Bantscheff M, Cox C, Gordon DA, Willard RR, Flanagan JJ, Casillas LN, Votta BJ, den Besten W, Famm K, Kruidenier L, Carter PS, Harling JD, Churcher I, Crews CM
Nat Chem Biol. 2015 11(8):611-7.

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4.
Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K, Crews CM
Chem Biol. 2015 22(6):755-63.

Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs.
Hines J, Gough JD, Corson TW, Crews CM
Proc Natl Acad Sci U S A. 2013 110(22):8942-7.

Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer.
Rodriguez-Gonzalez A, Cyrus K, Salcius M, Kim K, Crews CM, Deshaies RJ, Sakamoto KM.
Oncogene. 2008 27(57):7201-11

Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics.
Schneekloth AR, Pucheault M, Tae HS, Crews CM
Bioorg Med Chem Lett. 2008 18(22):5904-8. doi: 10.1016/j.bmcl.2008.07.114.

Chemical genetic control of protein levels: selective in vivo targeted degradation.
Schneekloth JS Jr, Fonseca FN, Koldobskiy M, Mandal A, Deshaies R, Sakamoto K, Crews CM
J Am Chem Soc. 2004 126(12):3748-54.

Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation.
Sakamoto KM, Kim KB, Verma R, Ransick A, Stein B, Crews CM, Deshaies RJ.
Mol Cell Proteomics. 2003 2(12):1350-8.

Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.
Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ.
Proc Natl Acad Sci U S A. 2001 98(15):8554-9.

Relevant Reviews

Targeted protein degradation: elements of PROTAC design.
Paiva SL, Crews CM
Curr Opin Chem Biol. 2019 Jun;50:111-119. doi: 10.1016/j.cbpa.2019.02.022. Epub 2019 Apr 17. Review

PROteolysis TArgeting Chimeras (PROTACs) – Past, present and future.
Pettersson M, Crews CM
Drug Discov Today Technol. 2019 Apr;31:15-27. doi: 10.1016/j.ddtec.2019.01.002. Epub 2019 Feb 13. Review

Small-Molecule Modulation of Protein Homeostasis.
Burslem GM, Crews CM
Chemical Reviews. 2017 117(17):11269-11301

Targeted Protein Knockdown Using Small Molecule Degraders.
Raina K, Crews CM
Current Opinion in Chemical Biology. 2017 39:46-53

Targeted Protein Degradation: from Chemical Biology to Drug Discovery.
Cromm PM, Crews CM
Cell Chemical Biology. 2017 24(9):1181-1190

Targeted Protein Degradation by PROTACs.
Neklesa TK, Winkler JD, Crews CM
Pharmacology & Therapeutics. 2017 174:138-144

Waste Disposal- An attractive strategy for cancer therapy
Salami J, Crews CM
Science. 2017 355(6330):1163-1167

Proteolysis-Targeting Chimeras: Induced Protein Degradation as a Therapeutic Strategy
Ottis P, Crews CM
ACS Chemical Biology. 2017 10.1021/acschembio.6b01068

Induced Protein Degradation: An Emerging Drug Discovery Paradigm.
Lai AC, Crews CM
Nature Reviews Drug Discovery. 2017 16:101-114

Targeted Protein Degradation by Small Molecules.
Bondeson DP, Crews CM
Annual Review of Pharmacology and Toxicology. 2017 57:107-123

Small-Molecule PROTACS: New Approaches to Protein Degradation.
Toure M, Crews CM
Angewandte Chemie International Edition. 2016 55:2-10

Small Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System.
Buckley DL, and Crews CM
Angewandte Chem. Int. Ed.. 2014 53(9):2312-2330

Chemical biology: Greasy tags for protein removal.
Neklesa TK, Crews CM
Nature. 2012 487(19):308-309

Targeted Intracellular Protein Degradation as a Potential Therapeutic Strategy.
Schneekloth AR and Crews CM
New Frontiers in Chemical Biology: Enabling Drug Discovery (edited by Bunnage ME). 2010

Targeting the Undruggable Proteome: The Small Molecules of My Dreams.
Crews CM
Chemistry & Biology. 2010 17(6):551-555

Chemical inducers of targeted protein degradation.
Raina K, Crews CM
J. Biol. Chem.. 2010 285(15):11057-11060

Design and applications of bifunctional small molecules: why two heads are better than one.
Corson TW, Aberle N, Crews CM
ACS Chemical Biology. 2008 3(11):677-692

Chemical genetic control of protein levels: selective in vivo targeted degradation.
Schneekloth JS Jr., Fonseca F, Koldobskiy M, Mandal A, Deshaies R, Sakamoto K, Crews CM
JACS 2004 126 12 3748-3754