PROTACs: An Emerging Therapeutic Modality in Precision Medicine

Cell Chemical Biology - Tập 27 Số 8 - Trang 998-1014 - 2020
Dhanusha A. Nalawansha1, Craig M. Crews2,1,3
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA
2Department of Chemistry, Yale University, New Haven, CT 06511 USA
3Department of Pharmacology, Yale University, New Haven, CT 06511, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

Albert, 2019, Photoswitchable peptides for spatiotemporal control of biological functions, Chem. Commun. (Camb.), 55, 10192, 10.1039/C9CC03346G

An, 2018, Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs, EBioMedicine, 36, 553, 10.1016/j.ebiom.2018.09.005

An, 2019, Developing potent PROTACs tools for selective degradation of HDAC6 protein, Protein Cell, 10, 606, 10.1007/s13238-018-0602-z

Ankenbruck, 2018, Optochemical control of biological processes in cells and animals, Angew. Chem. Int. Ed., 57, 2768, 10.1002/anie.201700171

Asatsuma-Okumura, 2019, p63 is a cereblon substrate involved in thalidomide teratogenicity, Nat. Chem. Biol., 15, 1077, 10.1038/s41589-019-0366-7

Audia, 2016, Histone modifications and cancer, Cold Spring Harb. Perspect. Biol., 8, a019521, 10.1101/cshperspect.a019521

Bai, 2019, A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo, Cancer Cell, 36, 498, 10.1016/j.ccell.2019.10.002

Bassi, 2018, Modulating PCAF/GCN5 immune cell function through a PROTAC approach, ACS Chem. Biol., 13, 2862, 10.1021/acschembio.8b00705

BasuRay, 2019, Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis, Proc. Natl. Acad. Sci. U S A, 116, 9521, 10.1073/pnas.1901974116

Bensimon, 2020, Targeted degradation of SLC transporters reveals amenability of multi-pass transmembrane proteins to ligand-induced proteolysis, Cell Chem. Biol., 27, 728, 10.1016/j.chembiol.2020.04.003

Bieliauskas, 2008, Isoform-selective histone deacetylase inhibitors, Chem. Soc. Rev., 37, 1402, 10.1039/b703830p

Bond, 2020, Targeted degradation of oncogenic KRASG12C by VHL-recruiting PROTACs, ACS Cent. Sci, 10.1021/acscentsci.0c00411

Bondeson, 2017, Targeted protein degradation by small molecules, Annu. Rev. Pharmacol. Toxicol., 57, 107, 10.1146/annurev-pharmtox-010715-103507

Bondeson, 2015, Catalytic in vivo protein knockdown by small-molecule PROTACs, Nat. Chem. Biol., 11, 611, 10.1038/nchembio.1858

Bondeson, 2018, Lessons in PROTAC design from selective degradation with a promiscuous warhead, Cell Chem. Biol., 25, 78, 10.1016/j.chembiol.2017.09.010

Brand, 2019, Homolog-selective degradation as a strategy to probe the function of CDK6 in AML, Cell Chem. Biol., 26, 300, 10.1016/j.chembiol.2018.11.006

Buckley, 2012, Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha, Angew. Chem. Int. Ed., 51, 11463, 10.1002/anie.201206231

Buckley, 2015, HaloPROTACS: use of small molecule PROTACs to induce degradation of HaloTag fusion proteins, ACS Chem. Biol., 10, 1831, 10.1021/acschembio.5b00442

Buckley, 2012, Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1alpha interaction, J. Am. Chem. Soc., 134, 4465, 10.1021/ja209924v

Buhimschi, 2018, Targeting the C481S ibrutinib-resistance mutation in Bruton's tyrosine kinase using PROTAC-mediated degradation, Biochemistry, 57, 3564, 10.1021/acs.biochem.8b00391

Burslem, 2017, Small-molecule modulation of protein homeostasis, Chem. Rev., 117, 11269, 10.1021/acs.chemrev.7b00077

Burslem, 2020, Proteolysis-targeting chimeras as therapeutics and tools for biological discovery, Cell, 181, 102, 10.1016/j.cell.2019.11.031

Burslem, 2019, Targeting BCR-ABL1 in chronic myeloid leukemia by PROTAC-mediated targeted protein degradation, Cancer Res., 79, 4744, 10.1158/0008-5472.CAN-19-1236

Burslem, 2018, The advantages of targeted protein degradation over inhibition: an RTK case study, Cell Chem. Biol., 25, 67, 10.1016/j.chembiol.2017.09.009

Burslem, 2018, Enhancing antiproliferative activity and selectivity of a FLT-3 inhibitor by proteolysis targeting chimera conversion, J. Am. Chem. Soc., 140, 16428, 10.1021/jacs.8b10320

Bussiere, 2020, Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex, Nat. Chem. Biol., 16, 15, 10.1038/s41589-019-0411-6

Cance, 2013, Disrupting the scaffold to improve focal adhesion kinase-targeted cancer therapeutics, Sci. Signal., 6, pe10, 10.1126/scisignal.2004021

Cartron, 2020, Epigenetic protein complexes: the adequate candidates for the use of a new generation of epidrugs in personalized and precision medicine in cancer, Epigenomics, 12, 171, 10.2217/epi-2019-0169

Chamberlain, 2019, Development of targeted protein degradation therapeutics, Nat. Chem. Biol., 15, 937, 10.1038/s41589-019-0362-y

Churcher, 2018, Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones?, J. Med. Chem., 61, 444, 10.1021/acs.jmedchem.7b01272

Coomar, 2019, Exploring DCAF15 for reprogrammable targeted protein degradation, bioRxiv, 542506

Crew, 2018, Identification and characterization of von Hippel-Lindau-recruiting proteolysis targeting chimeras (PROTACs) of TANK-binding kinase 1, J. Med. Chem., 61, 583, 10.1021/acs.jmedchem.7b00635

Crews, 2010, Targeting the undruggable proteome: the small molecules of my dreams, Chem. Biol., 17, 551, 10.1016/j.chembiol.2010.05.011

Cromm, 2018, Addressing kinase-independent functions of Fak via PROTAC-mediated degradation, J. Am. Chem. Soc., 140, 17019, 10.1021/jacs.8b08008

Cunningham, 1997, Autophosphorylation of activation loop tyrosines regulates signaling by the TRK nerve growth factor receptor, J. Biol. Chem., 272, 10957, 10.1074/jbc.272.16.10957

Demizu, 2012, Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy, Bioorg. Med. Chem. Lett., 22, 1793, 10.1016/j.bmcl.2011.11.086

Demizu, 2016, Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand, Bioorg. Med. Chem. Lett., 26, 4865, 10.1016/j.bmcl.2016.09.041

Ding, 2013, Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development, J. Med. Chem., 56, 5979, 10.1021/jm400487c

Dong, 2019, An allosteric PRC2 inhibitor targeting EED suppresses tumor progression by modulating the immune response, Cancer Res., 79, 5587, 10.1158/0008-5472.CAN-19-0428

Donovan, 2018, Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome, eLife, 7, e38430, 10.7554/eLife.38430

Du, 2019, Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820, Structure, 27, 1625, 10.1016/j.str.2019.10.005

Edgar, 2010, Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors, Cancer Res., 70, 1164, 10.1158/0008-5472.CAN-09-2525

Farnaby, 2019, BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design, Nat. Chem. Biol., 15, 672, 10.1038/s41589-019-0294-6

Faust, 2020, Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15, Nat. Chem. Biol., 16, 7, 10.1038/s41589-019-0378-3

Finley, 2009, Recognition and processing of ubiquitin-protein conjugates by the proteasome, Annu. Rev. Biochem., 78, 477, 10.1146/annurev.biochem.78.081507.101607

Fischer, 2014, Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide, Nature, 512, 49, 10.1038/nature13527

Fry, 2004, Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts, Mol. Cancer Ther., 3, 1427, 10.1158/1535-7163.1427.3.11

Gabizon, 2020, Efficient targeted degradation via reversible and irreversible covalent PROTACs, J. Am. Chem. Soc., 142, 11734, 10.1021/jacs.9b13907

Gadd, 2017, Structural basis of PROTAC cooperative recognition for selective protein degradation, Nat. Chem. Biol., 13, 514, 10.1038/nchembio.2329

Gao, 2020, PROTAC technology: opportunities and challenges, ACS Med. Chem. Lett., 11, 237, 10.1021/acsmedchemlett.9b00597

Gechijian, 2018, Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands, Nat. Chem. Biol., 14, 405, 10.1038/s41589-018-0010-y

Gehringer, 2019, Emerging and Re-emerging warheads for targeted covalent inhibitors: applications in medicinal chemistry and chemical biology, J. Med. Chem., 62, 5673, 10.1021/acs.jmedchem.8b01153

Goodnow, 2017, DNA-encoded chemistry: enabling the deeper sampling of chemical space, Nat. Rev. Drug Discov., 16, 131, 10.1038/nrd.2016.213

Han, 2013, ZNF313 is a novel cell cycle activator with an E3 ligase activity inhibiting cellular senescence by destabilizing p21(WAF1.), Cell Death Differ., 20, 1055, 10.1038/cdd.2013.33

Han, 2017, Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15, Science, 356, eaal3755, 10.1126/science.aal3755

Han, 2019, Discovery of ARD-69 as a highly potent proteolysis targeting chimera (PROTAC) degrader of androgen receptor (AR) for the treatment of prostate cancer, J. Med. Chem., 62, 941, 10.1021/acs.jmedchem.8b01631

Han, 2019, Discovery of highly potent and efficient PROTAC degraders of androgen receptor (AR) by employing weak binding affinity VHL E3 ligase ligands, J. Med. Chem., 62, 11218, 10.1021/acs.jmedchem.9b01393

He, 2020, Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity, Nat. Commun., 11, 1996, 10.1038/s41467-020-15838-0

Helin, 2013, Chromatin proteins and modifications as drug targets, Nature, 502, 480, 10.1038/nature12751

Hines, 2013, Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs, Proc. Natl. Acad. Sci. U S A, 110, 8942, 10.1073/pnas.1217206110

Hines, 2019, MDM2-Recruiting PROTAC offers superior, synergistic antiproliferative activity via simultaneous degradation of BRD4 and stabilization of p53, Cancer Res., 79, 251, 10.1158/0008-5472.CAN-18-2918

Hipp, 2019, The proteostasis network and its decline in ageing, Nat. Rev. Mol. Cell Biol., 20, 421, 10.1038/s41580-019-0101-y

Hon, 2002, Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL, Nature, 417, 975, 10.1038/nature00767

Hsu, 2020, EED-targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex, Cell Chem. Biol., 27, 41, 10.1016/j.chembiol.2019.11.004

Hu, 2019, Discovery of ERD-308 as a highly potent proteolysis targeting chimera (PROTAC) degrader of estrogen receptor (ER), J. Med. Chem., 62, 1420, 10.1021/acs.jmedchem.8b01572

Huang, 2018, A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader, Cell Chem. Biol., 25, 88, 10.1016/j.chembiol.2017.10.005

Humphreys, 2017, Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/General control nonderepressible 5 (GCN5) bromodomain chemical probe, J. Med. Chem., 60, 695, 10.1021/acs.jmedchem.6b01566

Ishoey, 2018, Translation termination factor GSPT1 is a phenotypically relevant off-target of heterobifunctional phthalimide degraders, ACS Chem. Biol., 13, 553, 10.1021/acschembio.7b00969

Ito, 2010, Identification of a primary target of thalidomide teratogenicity, Science, 327, 1345, 10.1126/science.1177319

Itoh, 2010, Protein knockdown using methyl bestatin-ligand hybrid molecules: design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins, J. Am. Chem. Soc., 132, 5820, 10.1021/ja100691p

Itoh, 2011, Design, synthesis and biological evaluation of nuclear receptor-degradation inducers, Bioorg. Med. Chem., 19, 6768, 10.1016/j.bmc.2011.09.041

Jacquemard, 2019, A bright future for fragment-based drug discovery: what does it hold?, Expert Opin. Drug Discov., 14, 413, 10.1080/17460441.2019.1583643

Jain, 2010, p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription, J. Biol. Chem., 285, 22576, 10.1074/jbc.M110.118976

Jiang, 2019, Development of dual and selective degraders of cyclin-dependent kinases 4 and 6, Angew. Chem. Int. Ed., 58, 6321, 10.1002/anie.201901336

Jin, 2020, Azo-PROTAC: novel light-controlled small-molecule tool for protein knockdown, J. Med. Chem., 63, 4644, 10.1021/acs.jmedchem.9b02058

Khan, 2019, A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity, Nat. Med., 25, 1938, 10.1038/s41591-019-0668-z

Kim, 2013, Molecular chaperone functions in protein folding and proteostasis, Annu. Rev. Biochem., 82, 323, 10.1146/annurev-biochem-060208-092442

Kliza, 2020, Resolving the complexity of ubiquitin networks, Front Mol. Biosci., 7, 21, 10.3389/fmolb.2020.00021

Kobayashi, 2004, Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2, Mol. Cell. Biol., 24, 7130, 10.1128/MCB.24.16.7130-7139.2004

Konstantinidou, 2019, PROTACs- a game-changing technology, Expert Opin. Drug Discov., 14, 1255, 10.1080/17460441.2019.1659242

Kostic, 2020, Critical assessment of targeted protein degradation as a research tool and pharmacological modality, Trends Pharmacol. Sci., 41, 305, 10.1016/j.tips.2020.02.006

Kouhara, 1997, A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway, Cell, 89, 693, 10.1016/S0092-8674(00)80252-4

Kounde, 2020, A caged E3 ligase ligand for PROTAC-mediated protein degradation with light, Chem. Commun. (Camb.), 56, 5532, 10.1039/D0CC00523A

Kronke, 2015, Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS, Nature, 523, 183, 10.1038/nature14610

Kronke, 2014, Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells, Science, 343, 301, 10.1126/science.1244851

Kumar Deshmukh, 2019, The contribution of the 20S proteasome to proteostasis, Biomolecules, 9, 190, 10.3390/biom9050190

Kurihara, 2020, Cereblon-mediated degradation of the amyloid precursor protein via the ubiquitin-proteasome pathway, Biochem. Biophys. Res. Commun., 524, 236, 10.1016/j.bbrc.2020.01.078

Kwon, 2019, AMPK is down-regulated by the CRL4A-CRBN axis through the polyubiquitination of AMPKα isoforms, FASEB J., 33, 6539, 10.1096/fj.201801766RRR

Lai, 2017, Induced protein degradation: an emerging drug discovery paradigm, Nat. Rev. Drug Discov., 16, 101, 10.1038/nrd.2016.211

Lai, 2016, Modular PROTAC design for the degradation of oncogenic BCR-ABL, Angew. Chem. Int. Ed., 55, 807, 10.1002/anie.201507634

Laugesen, 2016, Role of the polycomb repressive complex 2 (PRC2) in transcriptional regulation and cancer, Cold Spring Harb. Perspect. Med., 6, a026575, 10.1101/cshperspect.a026575

Lee, 2015, FAK signaling in human cancer as a target for therapeutics, Pharmacol. Ther., 146, 132, 10.1016/j.pharmthera.2014.10.001

Lee, 2007, DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase, Mol. Cell, 26, 775, 10.1016/j.molcel.2007.06.001

Lemmon, 2010, Cell signaling by receptor tyrosine kinases, Cell, 141, 1117, 10.1016/j.cell.2010.06.011

Li, 2001, Neuregulin signaling through a PI3K/Akt/Bad pathway in Schwann cell survival, Mol. Cell Neurosci., 17, 761, 10.1006/mcne.2000.0967

Li, 2019, Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression, J. Med. Chem., 62, 448, 10.1021/acs.jmedchem.8b00909

Li, 2020, First small-molecule PROTACs for G protein-coupled receptors: inducing α1A-adrenergic receptor degradation, Acta Pharm. Sin. B

Li, 2020, Development and characterization of a Wee1 kinase degrader, Cell Chem. Biol., 27, 57, 10.1016/j.chembiol.2019.10.013

Liby, 2012, Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease, Pharmacol. Rev., 64, 972, 10.1124/pr.111.004846

Liu, 2020, Light-induced control of protein destruction by opto-PROTAC, Sci. Adv., 6, eaay5154, 10.1126/sciadv.aay5154

Lu, 2015, Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4, Chem. Biol., 22, 755, 10.1016/j.chembiol.2015.05.009

Lu, 2018, Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway, Eur. J. Med. Chem., 146, 251, 10.1016/j.ejmech.2018.01.063

Maneiro, 2020, Antibody-PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4, ACS Chem. Biol., 15, 1306, 10.1021/acschembio.0c00285

Mares, 2020, Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2, Commun. Biol., 3, 140, 10.1038/s42003-020-0868-6

Matyskiela, 2016, A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase, Nature, 535, 252, 10.1038/nature18611

Moon, 2018, Chemically induced cellular proteolysis: an emerging therapeutic strategy for undruggable targets, Mol. Cells, 41, 933

Mullard, 2019, First targeted protein degrader hits the clinic, Nat. Rev. Drug Discov., 18, 237

Murtuza, 2019, Novel third-generation EGFR tyrosine kinase inhibitors and strategies to overcome therapeutic resistance in lung cancer, Cancer Res., 79, 689, 10.1158/0008-5472.CAN-18-1281

Nagy, 2007, Distinct GCN5/PCAF-containing complexes function as co-activators and are involved in transcription factor and global histone acetylation, Oncogene, 26, 5341, 10.1038/sj.onc.1210604

Naito, 2019, SNIPERs—hijacking IAP activity to induce protein degradation, Drug Discov. Today Tech., 31, 35, 10.1016/j.ddtec.2018.12.002

Naro, 2020, Optical control of small molecule-induced protein degradation, J. Am. Chem. Soc., 142, 2193, 10.1021/jacs.9b12718

Neklesa, 2017, Targeted protein degradation by PROTACs, Pharmacol. Ther., 174, 138, 10.1016/j.pharmthera.2017.02.027

Nguyen, 2020, Targeting the E3 ubiquitin ligases DCAF15 and cereblon for cancer therapy, Semin. Cancer Biol., 10.1016/j.semcancer.2020.03.007

Nguyen, 2016, Glutamine triggers acetylation-dependent degradation of glutamine synthetase via the thalidomide receptor cereblon, Mol. Cell, 61, 809, 10.1016/j.molcel.2016.02.032

Ohoka, 2014, Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway, Cell Death Dis., 5, e1513, 10.1038/cddis.2014.471

Ohoka, 2017, In vivo knockdown of pathogenic proteins via specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), J. Biol. Chem., 292, 4556, 10.1074/jbc.M116.768853

Ottis, 2017, Proteolysis-targeting chimeras: induced protein degradation as a therapeutic strategy, ACS Chem. Biol., 12, 892, 10.1021/acschembio.6b01068

Ottis, 2019, Cellular resistance mechanisms to targeted protein degradation converge toward impairment of the engaged ubiquitin transfer pathway, ACS Chem. Biol., 14, 2215

Ottis, 2017, Assessing different E3 ligases for small molecule induced protein ubiquitination and degradation, ACS Chem. Biol., 12, 2570, 10.1021/acschembio.7b00485

Pfaff, 2019, Reversible spatiotemporal control of induced protein degradation by bistable PhotoPROTACs, ACS Cent. Sci., 5, 1682, 10.1021/acscentsci.9b00713

Popow, 2019, Highly selective PTK2 proteolysis targeting chimeras to probe focal adhesion kinase scaffolding functions, J. Med. Chem., 62, 2508, 10.1021/acs.jmedchem.8b01826

Potjewyd, 2020, Degradation of polycomb repressive complex 2 with an EED-targeted bivalent chemical degrader, Cell Chem. Biol., 27, 47, 10.1016/j.chembiol.2019.11.006

Powell, 2018, Chemically induced degradation of anaplastic lymphoma kinase (ALK), J. Med. Chem., 61, 4249, 10.1021/acs.jmedchem.7b01655

Qi, 2017, An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED, Nat. Chem. Biol., 13, 381, 10.1038/nchembio.2304

Raina, 2017, Targeted protein knockdown using small molecule degraders, Curr. Opin. Chem. Biol., 39, 46, 10.1016/j.cbpa.2017.05.016

Raina, 2016, PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer, Proc. Natl. Acad. Sci. U S A, 113, 7124, 10.1073/pnas.1521738113

Rana, 2019, Selective degradation of CDK6 by a palbociclib based PROTAC, Bioorg. Med. Chem. Lett., 29, 1375, 10.1016/j.bmcl.2019.03.035

Renicke, 2013, A LOV2 domain-based optogenetic tool to control protein degradation and cellular function, Chem. Biol., 20, 619, 10.1016/j.chembiol.2013.03.005

Reynders, 2020, PHOTACs enable optical control of protein degradation, Sci. Adv., 6, eaay5064, 10.1126/sciadv.aay5064

Roy, 2019, SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate, ACS Chem. Biol., 14, 361, 10.1021/acschembio.9b00092

Sakamoto, 2001, Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation, Proc. Natl. Acad. Sci. U S A, 98, 8554, 10.1073/pnas.141230798

Sakamoto, 2003, Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol. Cell. Proteomics, 2, 1350, 10.1074/mcp.T300009-MCP200

Salami, 2018, Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance, Commun. Biol., 1, 100, 10.1038/s42003-018-0105-8

Salami, 2017, Waste disposal–An attractive strategy for cancer therapy, Science, 355, 1163, 10.1126/science.aam7340

Schapira, 2019, Targeted protein degradation: expanding the toolbox, Nat. Rev. Drug Discov., 18, 949, 10.1038/s41573-019-0047-y

Schiedel, 2018, Chemically induced degradation of sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals), J. Med. Chem., 61, 482, 10.1021/acs.jmedchem.6b01872

Schneekloth, 2008, Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics, Bioorg. Med. Chem. Lett., 18, 5904, 10.1016/j.bmcl.2008.07.114

Schneekloth, 2004, Chemical genetic control of protein levels: selective in vivo targeted degradation, J. Am. Chem. Soc., 126, 3748, 10.1021/ja039025z

Sievers, 2018, Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN, Science, 362, eaat0572, 10.1126/science.aat0572

Silva, 2019, Light-triggered release of photocaged therapeutics - where are we now?, J. Controll. Release, 298, 154, 10.1016/j.jconrel.2019.02.006

Silva, 2019, Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models, eLife, 8, eaat0572, 10.7554/eLife.45457

Smalley, 2020, PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes, Chem. Commun. (Camb.), 56, 4476, 10.1039/D0CC01485K

Smith, 2019, Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase, Nat. Commun., 10, 131, 10.1038/s41467-018-08027-7

Sporn, 2011, New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress, J. Nat. Prod., 74, 537, 10.1021/np100826q

Spradlin, 2019, Harnessing the anti-cancer natural product nimbolide for targeted protein degradation, Nat. Chem. Biol., 15, 747, 10.1038/s41589-019-0304-8

St Pierre, 2017, Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities, Curr. Opin. Genet. Dev., 42, 56, 10.1016/j.gde.2017.02.004

Tatham, 2008, RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation, Nat. Cell Biol., 10, 538, 10.1038/ncb1716

Ting, 2019, Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15, Cell Rep., 29, 1499, 10.1016/j.celrep.2019.09.079

Tinworth, 2019, PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding, ACS Chem. Biol., 14, 342, 10.1021/acschembio.8b01094

Tong, 2020, Targeted protein degradation via a covalent reversible degrader based on bardoxolone, ChemRxiv

Tong, 2020, A nimbolide-based kinase degrader preferentially degrades oncogenic BCR-ABL, ACS Chem. Biol., 15, 1788, 10.1021/acschembio.0c00348

Tovar, 2006, Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy, Proc. Natl. Acad. Sci. U S A, 103, 1888, 10.1073/pnas.0507493103

Tovell, 2019, Design and characterization of SGK3-PROTAC1, an isoform specific SGK3 kinase PROTAC degrader, ACS Chem. Biol., 14, 2024, 10.1021/acschembio.9b00505

Uehara, 2017, Selective degradation of splicing factor CAPERalpha by anticancer sulfonamides, Nat. Chem. Biol., 13, 675, 10.1038/nchembio.2363

Verma, 2020, Harnessing the power of proteolysis for targeted protein inactivation, Mol. Cell, 77, 446, 10.1016/j.molcel.2020.01.010

Vogelmann, 2020, Proteolysis targeting chimeras (PROTACs) for epigenetics research, Curr. Opin. Chem. Biol., 57, 8, 10.1016/j.cbpa.2020.01.010

Wang, 2019, Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation, Nat. Chem. Biol., 15, 1223, 10.1038/s41589-019-0379-2

Wang, 2017, Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: progress and challenges, Cold Spring Harb. Perspect. Med., 7, a026245, 10.1101/cshperspect.a026245

Wang, 2019, Proteolysis targeting chimeras for the selective degradation of mcl-1/Bcl-2 derived from nonselective target binding ligands, J. Med. Chem., 62, 8152, 10.1021/acs.jmedchem.9b00919

Ward, 2019, Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications, ACS Chem. Biol., 14, 2430, 10.1021/acschembio.8b01083

Weerapana, 2010, Quantitative reactivity profiling predicts functional cysteines in proteomes, Nature, 468, 790, 10.1038/nature09472

Winter, 2015, DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation, Science, 348, 1376, 10.1126/science.aab1433

Wu, 2019, Development of multifunctional histone deacetylase 6 degraders with potent antimyeloma activity, J. Med. Chem., 62, 7042, 10.1021/acs.jmedchem.9b00516

Xiong, 2017, Discovery of potent and selective inhibitors for G9a-like protein (GLP) lysine methyltransferase, J. Med. Chem., 60, 1876, 10.1021/acs.jmedchem.6b01645

Xue, 2020, Protein degradation through covalent inhibitor-based PROTACs, Chem. Commun. (Camb.), 56, 1521, 10.1039/C9CC08238G

Xue, 2019, Light-induced protein degradation with photocaged PROTACs, J. Am. Chem. Soc., 141, 18370, 10.1021/jacs.9b06422

Yang, 2016, Differential expression of p38 MAPK α, β, γ, δ isoforms in nucleus pulposus modulates macrophage polarization in intervertebral disc degeneration, Sci. Rep., 6, 22182, 10.1038/srep22182

Yang, 2018, Development of the first small molecule histone deacetylase 6 (HDAC6) degraders, Bioorg. Med. Chem. Lett., 28, 2493, 10.1016/j.bmcl.2018.05.057

Yang, 2020, A cell-based target engagement assay for the identification of cereblon E3 ubiquitin ligase ligands and their application in HDAC6 degraders, Cell Chem. Biol., 27, 866, 10.1016/j.chembiol.2020.04.008

Zengerle, 2015, Selective small molecule induced degradation of the BET bromodomain protein BRD4, ACS Chem. Biol., 10, 1770, 10.1021/acschembio.5b00216

Zhang, 2004, Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex, Mol. Cell. Biol., 24, 10941, 10.1128/MCB.24.24.10941-10953.2004

Zhang, 2019, Acquired resistance to BET-PROTACs (proteolysis targeting chimeras) caused by genomic alterations in core components of E3 ligase complexes, Mol. Cancer Ther., 18, 1302, 10.1158/1535-7163.MCT-18-1129

Zhang, 2019, Recent advances in selective and irreversible covalent ligand development and validation, Cell Chem. Biol., 26, 1486, 10.1016/j.chembiol.2019.09.012

Zhang, 2019, Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16, Nat. Chem. Biol., 15, 737, 10.1038/s41589-019-0279-5

Zhang, 2020, Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines, Eur. J. Med. Chem., 199, 112397, 10.1016/j.ejmech.2020.112397

Zhang, 2020, Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity, Eur. J. Med. Chem., 192, 112186, 10.1016/j.ejmech.2020.112186

Zhou, 2020, Development of selective mono or dual PROTAC degrader probe of CDK isoforms, Eur. J. Med. Chem., 187, 111952, 10.1016/j.ejmech.2019.111952

Zoppi, 2019, Iterative design and optimization of initially inactive proteolysis targeting chimeras (PROTACs) identify VZ185 as a potent, fast, and selective von Hippel-Lindau (VHL) based dual degrader probe of BRD9 and BRD7, J. Med. Chem., 62, 699, 10.1021/acs.jmedchem.8b01413