Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery

Cell - Tập 181 Số 1 - Trang 102-114 - 2020
George M. Burslem1, Craig M. Crews1,2
1Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT USA
2Departments of Chemistry and Pharmacology, Yale University, New Haven, CT, USA

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Agrawal, 2003, RNA interference: biology, mechanism, and applications, Microbiol. Mol. Biol. Rev., 67, 657, 10.1128/MMBR.67.4.657-685.2003

Altmann, 2009, The state of the art of chemical biology, ChemBioChem, 10, 16, 10.1002/cbic.200800758

Amm, 2014, Protein quality control and elimination of protein waste: the role of the ubiquitin-proteasome system, Biochim. Biophys. Acta, 1843, 182, 10.1016/j.bbamcr.2013.06.031

Ardley, 2005, E3 ubiquitin ligases, Essays Biochem., 41, 15, 10.1042/EB0410015

Argiropoulos, 2007, Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis, Genes Dev., 21, 2845, 10.1101/gad.1619407

Backus, 2016, Proteome-wide covalent ligand discovery in native biological systems, Nature, 534, 570, 10.1038/nature18002

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

Boija, 2018, Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains, Cell, 175, 1842, 10.1016/j.cell.2018.10.042

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

Botstein, 2010, Technological innovation leads to fundamental understanding in cell biology, Mol. Biol. Cell, 21, 3791, 10.1091/mbc.e10-04-0366

Brand, 2019, Locus-Specific Knock-In of a Degradable Tag for Target Validation Studies, 105

Brien, 2018, Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma, eLife, 7, e41305, 10.7554/eLife.41305

Brownell, 2010, Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ, Mol. Cell, 37, 102, 10.1016/j.molcel.2009.12.024

Brunetti, 2018, Mutant NPM1 Maintains the Leukemic State through HOX Expression, Cancer Cell, 34, 499, 10.1016/j.ccell.2018.08.005

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

Buckley, 2015, HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins, ACS Chem. Biol., 10, 1831, 10.1021/acschembio.5b00442

Burslem, 2017, Small-Molecule Modulation of Protein Homeostasis, Chem. Rev., 117, 11269, 10.1021/acs.chemrev.7b00077

Burslem, 2017, Hypoxia inducible factor (HIF) as a model for studying inhibition of protein-protein interactions, Chem. Sci. (Camb.), 8, 4188, 10.1039/C7SC00388A

Burslem, 2018, Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure-Degradation Relationships, ChemMedChem, 13, 1508, 10.1002/cmdc.201800271

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

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

Carter, 2019, Target 2035: probing the human proteome, Drug Discov. Today, 24, 2111, 10.1016/j.drudis.2019.06.020

Chu, 2016, Specific Knockdown of Endogenous Tau Protein by Peptide-Directed Ubiquitin-Proteasome Degradation, Cell Chem. Biol., 23, 453, 10.1016/j.chembiol.2016.02.016

Clackson, 1998, Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity, Proc. Natl. Acad. Sci. USA, 95, 10437, 10.1073/pnas.95.18.10437

Clift, 2017, A Method for the Acute and Rapid Degradation of Endogenous Proteins, Cell, 171, 1692, 10.1016/j.cell.2017.10.033

Corbin, 2011, Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity, J. Clin. Invest., 121, 396, 10.1172/JCI35721

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

Cromm, 2018, Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation, J. Am. Chem. Soc., 140, 17019, 10.1021/jacs.8b08008

Douglass, 2013, A comprehensive mathematical model for three-body binding equilibria, J. Am. Chem. Soc., 135, 6092, 10.1021/ja311795d

Druker, 2009, Perspectives on the development of imatinib and the future of cancer research, Nat. Med., 15, 1149, 10.1038/nm1009-1149

Editorial, 2000, The importance of technological advances, Nat. Cell Biol., 2, E37, 10.1038/35004064

England, 2015, HaloTag technology: a versatile platform for biomedical applications, Bioconjug. Chem., 26, 975, 10.1021/acs.bioconjchem.5b00191

Erb, 2017, Transcription control by the ENL YEATS domain in acute leukaemia, Nature, 543, 270, 10.1038/nature21688

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

Field, 2017, Selective Downregulation of JAK2 and JAK3 by an ATP-Competitive pan-JAK Inhibitor, ACS Chem. Biol., 12, 1183, 10.1021/acschembio.7b00116

Fields, 2001, The interplay of biology and technology, Proc. Natl. Acad. Sci. USA, 98, 10051, 10.1073/pnas.191380098

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

Flanagan, 2019, Targeting Nuclear Receptors with PROTAC degraders, Mol. Cell. Endocrinol., 493, 110452, 10.1016/j.mce.2019.110452

Flanagan, 2019, ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer, Cancer Research, 79, 10.1158/1538-7445.SABCS18-P5-04-18

Frost, 2016, Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition, Nat. Commun., 7, 13312, 10.1038/ncomms13312

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

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

Grice, 2016, The recognition of ubiquitinated proteins by the proteasome, Cell. Mol. Life Sci., 73, 3497, 10.1007/s00018-016-2255-5

Grunwald, 2013, FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance, Int. J. Hematol., 97, 683, 10.1007/s12185-013-1334-8

Gustafson, 2015, Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging, Angew. Chem. Int. Ed. Engl., 54, 9659, 10.1002/anie.201503720

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

Hebbard, 2010, Maternal embryonic leucine zipper kinase is upregulated and required in mammary tumor-initiating cells in vivo, Cancer Res., 70, 8863, 10.1158/0008-5472.CAN-10-1295

Hellerschmied, 2019, Protein Folding State-dependent Sorting at the Golgi Apparatus, Mol. Biol. Cell, 30, 2296, 10.1091/mbc.E19-01-0069

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

Hopkins, 2002, The druggable genome, Nat. Rev. Drug Discov., 1, 727, 10.1038/nrd892

Howell, 2004, The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer, Best Pract. Res. Clin. Endocrinol. Metab., 18, 47, 10.1016/j.beem.2003.08.002

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, 2017, MELK is not necessary for the proliferation of basal-like breast cancer cells, eLife, 6, e26693, 10.7554/eLife.26693

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

Iadanza, 2018, A new era for understanding amyloid structures and disease, Nat. Rev. Mol. Cell Biol., 19, 755, 10.1038/s41580-018-0060-8

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

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

Jacobsen, 2009, Transcriptional effects of transfection: the potential for misinterpretation of gene expression data generated from transiently transfected cells, Biotechniques, 47, 617, 10.2144/000113132

Jain, 2019, Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma, Sci. Transl. Med., 11, eaav5599, 10.1126/scitranslmed.aav5599

Kim, 2013, From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes, Nat. Prod. Rep., 30, 600, 10.1039/c3np20126k

Kleiger, 2014, Perilous journey: a tour of the ubiquitin-proteasome system, Trends Cell Biol., 24, 352, 10.1016/j.tcb.2013.12.003

Komander, 2012, The ubiquitin code, Annu. Rev. Biochem., 81, 203, 10.1146/annurev-biochem-060310-170328

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

Lai, 2016, Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL, Angew. Chem. Int. Ed. Engl., 55, 807, 10.1002/anie.201507634

Leonetti, 2016, A scalable strategy for high-throughput GFP tagging of endogenous human proteins, Proc. Natl. Acad. Sci. USA, 113, E3501, 10.1073/pnas.1606731113

Los, 2008, HaloTag: a novel protein labeling technology for cell imaging and protein analysis, ACS Chem. Biol., 3, 373, 10.1021/cb800025k

Lu, 2015, Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4, Chem. Biol., 22, 755, 10.1016/j.chembiol.2015.05.009

Martin, 2019, PHOTACs Enable Optical Control of Protein Degradation, ChemRxiv

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

McDonald, 2017, Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening, Cell, 170, 577, 10.1016/j.cell.2017.07.005

Michel, 2018, A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation, Nat. Cell Biol., 20, 1410, 10.1038/s41556-018-0221-1

Nabet, 2018, The dTAG system for immediate and target-specific protein degradation, Nat. Chem. Biol., 14, 431, 10.1038/s41589-018-0021-8

Neklesa, 2011, Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins, Nat. Chem. Biol., 7, 538, 10.1038/nchembio.597

Neklesa, 2019, ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer, J. Clin. Oncol., 37, 259, 10.1200/JCO.2019.37.7_suppl.259

Nowak, 2018, Plasticity in binding confers selectivity in ligand-induced protein degradation, Nat. Chem. Biol., 14, 706, 10.1038/s41589-018-0055-y

Nunes, 2019, Targeting IRAK4 for Degradation with PROTACs, ACS Med. Chem. Lett., 10, 1081, 10.1021/acsmedchemlett.9b00219

Omenn, 2018, Progress on Identifying and Characterizing the Human Proteome: 2018 Metrics from the HUPO Human Proteome Project, J. Proteome Res., 17, 4031, 10.1021/acs.jproteome.8b00441

Ottis, 2017, Assessing Different E3 Ligases for Small Molecule Induced Protein Ubiquitination and Degradation, ACS Chem. Biol., 12, 2570, 10.1021/acschembio.7b00485

Ottis, 2019, Cellular Resistance Mechanisms to Targeted Protein Degradation Converge Toward Impairment of the Engaged Ubiquitin Transfer Pathway, ACS Chem. Biol., 14, 2215

Palmer, 2016, Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor, J. Med. Chem., 59, 1440, 10.1021/acs.jmedchem.5b00405

Paramore, 2003, Bortezomib, Nat. Rev. Drug Discov., 2, 611, 10.1038/nrd1159

Parker, 2017, Ligand and Target Discovery by Fragment-Based Screening in Human Cells, Cell, 168, 527, 10.1016/j.cell.2016.12.029

Patel, 2018, Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment, Pharmacol. Ther., 186, 1, 10.1016/j.pharmthera.2017.12.012

Piya, 2019, BETP degradation simultaneously targets acute myelogenous leukemia stem cells and the microenvironment, J. Clin. Invest., 129, 1878, 10.1172/JCI120654

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

Pratz, 2009, A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response, Blood, 113, 3938, 10.1182/blood-2008-09-177030

Raina, 2014, Targeted protein destabilization reveals an estrogen-mediated ER stress response, Nat. Chem. Biol., 10, 957, 10.1038/nchembio.1638

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

Rathkopf, 2013, Androgen receptor antagonists in castration-resistant prostate cancer, Cancer J., 19, 43, 10.1097/PPO.0b013e318282635a

Remillard, 2017, Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands, Angew. Chem. Int. Ed. Engl., 56, 5738, 10.1002/anie.201611281

Riching, 2018, Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action, ACS Chem. Biol., 13, 2758, 10.1021/acschembio.8b00692

Roy, 2019, SPR-Measured Dissociation Kinetics of PROTAC Ternary Complexes Influence Target Degradation Rate, ACS Chem. Biol., 14, 361, 10.1021/acschembio.9b00092

Saenz, 2017, Novel BET protein proteolysis targeting chimera (BET-PROTAC) exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm (MPN) secondary (s) AML cells, Leukemia, 31, 1951, 10.1038/leu.2016.393

Saenz, 2019, Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML, Leukemia, 33, 1373, 10.1038/s41375-018-0334-3

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

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

Savitski, 2018, Multiplexed Proteome Dynamics Profiling Reveals Mechanisms Controlling Protein Homeostasis, Cell, 173, 260, 10.1016/j.cell.2018.02.030

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

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

Sekine, 2008, Small molecules destabilize cIAP1 by activating auto-ubiquitylation, J. Biol. Chem., 283, 8961, 10.1074/jbc.M709525200

Serebrenik, 2018, Targeted protein unfolding uncovers a Golgi-specific transcriptional stress response, Mol. Biol. Cell, 29, 1284, 10.1091/mbc.E17-11-0693

Setten, 2019, The current state and future directions of RNAi-based therapeutics, Nat. Rev. Drug Discov., 18, 421, 10.1038/s41573-019-0017-4

Shibata, 2017, Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands, Cancer Sci., 108, 1657, 10.1111/cas.13284

Shibata, 2019, Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein, Chem. Pharm. Bull. (Tokyo), 67, 165, 10.1248/cpb.c18-00703

Silva, 2019, Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models, eLife, 8, e45457, 10.7554/eLife.45457

Sima, 2019, Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication, Cell, 176, 816, 10.1016/j.cell.2018.11.036

Smagris, 2015, Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis, Hepatology, 61, 108, 10.1002/hep.27242

Smith, 2011, Road to ruin: targeting proteins for degradation in the endoplasmic reticulum, Science, 334, 1086, 10.1126/science.1209235

Smith, 2012, Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia, Nature, 485, 260, 10.1038/nature11016

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

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

Sun, 2018, BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells, Leukemia, 32, 343, 10.1038/leu.2017.207

Sun, 2019, A chemical approach for global protein knockdown from mice to non-human primates, Cell Discov., 5, 10, 10.1038/s41421-018-0079-1

Tomoshige, 2015, Degradation of HaloTag-fused nuclear proteins using bestatin-HaloTag ligand hybrid molecules, Org. Biomol. Chem., 13, 9746, 10.1039/C5OB01395J

Tomoshige, 2016, Efficient protein knockdown of HaloTag-fused proteins using hybrid molecules consisting of IAP antagonist and HaloTag ligand, Bioorg. Med. Chem., 24, 3144, 10.1016/j.bmc.2016.05.035

Touré, 2016, Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight, J. Med. Chem., 59, 4711, 10.1021/acs.jmedchem.6b00052

Tovell, 2019, Rapid and Reversible Knockdown of Endogenously Tagged Endosomal Proteins via an Optimized HaloPROTAC Degrader, ACS Chem. Biol., 14, 882, 10.1021/acschembio.8b01016

Tsherniak, 2017, Defining a Cancer Dependency Map, Cell, 170, 564, 10.1016/j.cell.2017.06.010

van Steensel, 2015, A short guide to technology development in cell biology, J. Cell Biol., 208, 655, 10.1083/jcb.201502006

Visweshwaran, 2018, The trimeric coiled-coil HSBP1 protein promotes WASH complex assembly at centrosomes, EMBO J., 37, 97706, 10.15252/embj.201797706

Ward, 2019, Covalent Ligand Screening Uncovers an RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications, ACS Chem. Biol., 14, 2430, 10.1021/acschembio.8b01083

Wardell, 2011, The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy, Biochem. Pharmacol., 82, 122, 10.1016/j.bcp.2011.03.031

Weissmiller, 2019, Inhibition of MYC by the SMARCB1 tumor suppressor, Nat. Commun., 10, 2014, 10.1038/s41467-019-10022-5

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

Yang, 2019, Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins - A review, Drug Discov. Today. Technol., 31, 43, 10.1016/j.ddtec.2019.04.001

Yau, 2016, The increasing complexity of the ubiquitin code, Nat. Cell Biol., 18, 579, 10.1038/ncb3358

Zarrinkar, 2009, AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML), Blood, 114, 2984, 10.1182/blood-2009-05-222034

Zhang, 2018, Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma, Leukemia, 32, 2224, 10.1038/s41375-018-0044-x

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

Zorba, 2018, Delineating the role of cooperativity in the design of potent PROTACs for BTK, Proc. Natl. Acad. Sci. USA, 115, E7285, 10.1073/pnas.1803662115