PROTACs– a game-changing technology

References

• Sakamoto KM, Kim KB, Kumagai A, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci. USA. 2001;98(15):8554–8559. DOI:https://doi.org/10.1073/pnas.141230798.
   PubMed Web of Science ®Google Scholar
• Scudellari M. Protein-slaying drugs could be the next blockbuster therapies. Nature. 2019;567(7748):298–300.
   PubMedGoogle Scholar
• Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67(1):425–479.
   PubMedGoogle Scholar
• Salami J, Crews CM. Waste disposal-an attractive strategy for cancer therapy. Science. 2017;355(6330):1163–1167.
   PubMed Web of Science ®Google Scholar
• Nero TL, Morton CJ, Holien JK, et al. Oncogenic protein interafaces: small molecules, big challenges. Nat Rev Cancer. 2014;14(4):248–262.
   PubMed Web of Science ®Google Scholar
• Zhang QC, Petrey D, Deng L, et al. Structure-based prediction of protein-protein interactions on a genome-wide scale. Nature. 2012;490(7421):556–560.
   PubMed Web of Science ®Google Scholar
• Chessum NEA, Sharp SY, Caldwell JJ, et al. Demonstrating in-cell target engagement using a pirin protein degradation probe (CCT367766). J Med Chem. 2018;61(3):918–933.
   PubMed Web of Science ®Google Scholar
• Burslem GM, Smith BE, Lai AC, et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem Biol. 2018;25(1):67–77.
   PubMed Web of Science ®Google Scholar
• Bondeson DP, Mares A, Smith IE, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol. 2015;11(8):611–617.
   PubMed Web of Science ®Google Scholar
• Churcher I. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones? J Med Chem. 2018;61(2):444–452.
   PubMed Web of Science ®Google Scholar
• Sun X, Wang J, Yao X, et al. A chemical approach for global protein knockdown from mice to non-human primates. Cell Discov. 2019;5:10. eCollection 2019.
   PubMed Web of Science ®Google Scholar
• Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345–1350.
   PubMed Web of Science ®Google Scholar
• Lopez-Girona A, Mendy D, Ito T, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012;26(11):2326–2335.
   PubMed Web of Science ®Google Scholar
• Fischer ES, Böhm K, Lydeard JR, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014;512(7512):49–53.
   PubMed Web of Science ®Google Scholar
• Chamberlain PP, Lopez-Girona A, Miller K, et al. Structure of the human cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014;21(9):803–809.
   PubMed Web of Science ®Google Scholar
• Winter GE, Buckley DL, Paulk J, et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348(6241):1376–1381.
   PubMed Web of Science ®Google Scholar
• Lu J, Qian Y, Altieri M, et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. ChemBiol. 2015;22(6):755–763.
   PubMedGoogle Scholar
• Zhou B, Hu J, Xu F, et al. Discovery of a small molecule degrader of bromodomain and extra-terminal (BET) proteins with picomolar cellular potencies and capable of achieving tumor regression. J Med Chem. 2018;61(2):462–481.
   PubMed Web of Science ®Google Scholar
• Lai AC, Toure M, Hellerschmied D, et al. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew Chem Int Ed Engl. 2016;55(2):807–810.
   PubMed Web of Science ®Google Scholar
• Remillard D, Buckley DL, Paulk J, et al. Degradation of the BAF complex factor BRD9 by heterobifunctional ligands. Angew Chem Int Ed Engl. 2017;56(21):5738–5743.
   PubMed Web of Science ®Google Scholar
• Schiedel M, Herp D, Hammelmann S. et al. Chemically induced degradation of Sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuinrearranging ligands (SirReals). J Med Chem. 2018;61(2):482–491.
   PubMed Web of Science ®Google Scholar
• Olson CM, Jiang B, Erb MA, et al. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. Nat Chem Biol. 2018;14(2):163–170.
   PubMed Web of Science ®Google Scholar
• Robb CM, Contreras JI, Kour S, et al. Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). Chem Commun. 2017;53(54):7577–7580.
   PubMed Web of Science ®Google Scholar
• Huang HT, Dobrovolsky D, Paulk J, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol. 2018;25(1):88–99.
   PubMed Web of Science ®Google Scholar
• Buhimschi AD, Armstrong HA, Toure M, et al. the C481S ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation. Biochemistry. 2018;57(26):3564–3575.
   PubMed Web of Science ®Google Scholar
• Zhang C, Han XR, Yang X, et al. Proteolysis targeting chimeras (PROTACs) of anaplastic lymphoma kinase. (ALK) Eur J Med Chem. 2018;151:304–314.
   PubMed Web of Science ®Google Scholar
• Jiang B, Wang ES, Donovan KA, et al. Development of dual and selective degraders of cyclin-dependent kinases 4 and 6. Angew Chem Int Ed Engl. 2019;58(19):6321–6326.
   PubMed Web of Science ®Google Scholar
• Rana S, Bendjennat M, Kour S, et al. Selective degradation of CDK6 by a palbociclib based PROTAC. Bioorg Med Chem Lett. 2019;29(11):1375–1379.
   PubMed Web of Science ®Google Scholar
• Yang K, Song Y, Xie H. et al. Development of the first small molecule histone deacetylase 6 (HDAC6) degraders. Bioorg Med Chem Lett. 2018;28(14):2493–2497.
   PubMed Web of Science ®Google Scholar
• Schneekloth JS Jr, Fonseca FN, Koldobskiy M, et al. Chemical genetic control of protein levels: selective in vivo targeted degradation. J Am Chem Soc. 2004;126(12):3748–3754.
   PubMed Web of Science ®Google Scholar
• Buckley DL, Van Molle I, Gareiss PC. et al. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction. J Am Chem Soc. 2012;134(10):4465–4468.
   PubMed Web of Science ®Google Scholar
• Buckley DL, Gustafson JL, Van Molle I, et al. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α. Angew Chem Int Ed Engl. 2012;51(46):11463–11467.
   PubMed Web of Science ®Google Scholar
• Galdeano C, Gadd MS, Soares P, et al. Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities. J Med Chem. 2014;57(20):8657–8663.
   PubMed Web of Science ®Google Scholar
• Buckley DL, Raina K, Darricarrere N, et al. HaloPROTACS: use of small molecule PROTACs to induce degradation of HaloTag fusion proteins.ACS. Chem Biol. 2015;10(8):1831–1837.
   Google Scholar
• Raina K, Lu J, Qian Y, et al. BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2016;113(26):7124–7129.
   PubMed Web of Science ®Google Scholar
• Zengerle M, Chan KH, Ciulli A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem Biol. 2015;10(8):1770–1777.
   PubMed Web of Science ®Google Scholar
• Crew AP, Raina K, Dong H. et al. Identification and characterization of von Hippel-Lindau-recruiting proteolysis targeting chimeras (PROTACs) of TANK-binding kinase 1. J Med Chem. 2018;61(2):583–598.
   PubMed Web of Science ®Google Scholar
• Gechijian LN, Buckley DL, Lawlor MA. et al. Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands. Nat ChemBiol. 2018;14(4):405–412.
   Google Scholar
• Vassilev LT, Vu BT, Graves B, et al. in vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303(5659):844–848.
   PubMed Web of Science ®Google Scholar
• Schneekloth AR, Pucheault M, Tae HS, et al. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg Med Chem Lett. 2008;18(22):5904–5908.
   PubMed Web of Science ®Google Scholar
• Hines J, Lartigue S, Dong H, et al. MDM2-recruiting PROTAC offers superior, synergistic antiproliferative activity via s simultaneous degradation of BRD4 and stabilization of p53. Cancer Res. 2019;79(1):251–262.
   PubMed Web of Science ®Google Scholar
• Itoh Y, Ishikawa M, Naito M, et al. 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. 2010;132(16):5820–5826.
   PubMed Web of Science ®Google Scholar
• Itoh Y, Ishikawa M, Kitaguchi R, et al. Double protein knockdown of cIAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist. Bioorg Med Chem Lett. 2012;22(13):4453–4457.
   PubMed Web of Science ®Google Scholar
• Okuhira K, Demizu Y, Hattori T, et al. Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. Cancer Sci. 2013;104(11):1492–1498.
   PubMed Web of Science ®Google Scholar
• Demizu Y, Okuhira K, Motoi H, et al. Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy. Bioorg Med Chem Lett. 2012;22(4):1793–1796.
   PubMed Web of Science ®Google Scholar
• Ohoka N, Nagai K, Hattori T, et al. Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway. Cell Death Dis. 2014;5:e1513.
   PubMed Web of Science ®Google Scholar
• Demizu Y, Shibata N, Hattori T, et al. Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand. Bioorg Med Chem Lett. 2016;26(20):4865–4869.
   PubMed Web of Science ®Google Scholar
• Ohoka N, Okuhira K, Ito M, et al. in vivo knockdown of pathogenic proteins via specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs). J Biol Chem. 2017;292(11):4556–4570.
   PubMed Web of Science ®Google Scholar
• Shibata N, Nagai K, Morita Y, et al. Development of protein degradation inducers of androgen receptor by conjugation of androgen receptor ligands and inhibitor of apoptosis protein ligands. J Med Chem. 2018;61(2):543–575.
   PubMed Web of Science ®Google Scholar
• Long MJ, Gollapalli DR, Hedstrom L. Inhibitor mediated protein degradation. Chem Biol. 2012;19(5):629–637.
   PubMedGoogle Scholar
• Shi Y, Long MJ, Rosenberg MM, et al. Boc3Arg-linked ligands induce degradation by localizing target proteins to the 20S proteasome. ACS ChemBiol. 2016;11(12):3328–3337.
   PubMed Web of Science ®Google Scholar
• Wang L, Guillen VS, Sharma N, et al. New class of selective estrogen receptor degraders (SERDs): expanding the toolbox of PROTAC degrons. ACS Med Chem Lett. 2018;9(8):803–808.
   PubMed Web of Science ®Google Scholar
• Gadd MS, Testa A, Lucas X, et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat Chem Biol. 2017; 13(5): 514–521.
   PubMed Web of Science ®Google Scholar
• Nowak RP, DeAngelo SL, Buckley D, et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat Chem Biol. 2018; 14(7): 706–714.
   PubMed Web of Science ®Google Scholar
• Smith BE, Wang SL, Jaime-Figueroa S, et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat Commun. 2019;10(1):131.
   PubMedGoogle Scholar
• Farnaby W, Koegl M, Roy MJ, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol. 2019;15(7):672–680.
   PubMed Web of Science ®Google Scholar
• Hartmann MD, Boichenko I, Coles M, et al. Thalidomide mimics uridine binding to an aromatic cage in cereblon. J Struct Biol. 2014;188(3):225–232.
   PubMed Web of Science ®Google Scholar
• Boichenko I, Bär K, Deiss S, et al. Chemical ligand space of cereblon. ACS Omega. 2018;3(9):11163–11171.
   PubMed Web of Science ®Google Scholar
• Matyskiela ME, Lu G, Ito T, et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature. 2016;535(7611):252–257.
   PubMed Web of Science ®Google Scholar
• Hansen JD, Condroski K, Correa M, et al. Protein degradation via CRL4CRBN ubiquitin ligase: discovery and structure-activity relationships of novel glutarimideanalogs that promote degradation of Aiolos and/or GSPT1. J Med Chem. 2018;61(2):492–503.
   PubMed Web of Science ®Google Scholar
• Matyskiela ME, Zhang W, Man HW, et al. A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos. J Med Chem. 2018;61(2):535–542.
   PubMed Web of Science ®Google Scholar
• Soares P, Gadd MS, Frost J, et al. Group-based optimization of potent and cell-active inhibitors of the von Hippel–Lindau (VHL) E3 ubiquitin ligase: structure–activity relationships leading to the chemical probe (2S,4R)-1-((S)-2-(1-cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298). J Med Chem. 2018;61(2):599–618.
   PubMed Web of Science ®Google Scholar
• Testa A, Lucas X, Castro GV, et al. 3-Fluoro-4-hydroxyprolines: synthesis, conformational analysis, and stereoselectiverecognition by the VHL E3 ubiquitin ligase for targeted protein degradation. J Am Chem Soc. 2018;140(29):9299–9313.
   PubMed Web of Science ®Google Scholar
• Lucas X, Van Molle I, Ciulli A. Surface probing by fragment-based screening and computational methods identifies ligandablepockets on the von Hippel-Lindau (VHL) E3 ubiquitin ligase. J Med Chem. 2018;61(16):7387–7393.
   PubMed Web of Science ®Google Scholar
• Drummond ML, Williams CI. In silico modeling of PROTAC-mediated ternary complexes: validation and application. J Chem Inf Model. 2019;59(4): 1634–1644 and references therein.
   PubMed Web of Science ®Google Scholar
• Hughes SJ, Ciulli A. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Essay Biochem. 2017;61(5):505–516.
   PubMed Web of Science ®Google Scholar
• An S, Fu L. Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs. EBioMedicne. 2018;36:553–556.
   PubMed Web of Science ®Google Scholar
• Roy MJ, Winkler S, Hughes SJ, et al. SPR-measured dissociation kinetic of PROTAC ternary complexes influence target degradation rate. ACS Chem Biol. 2019;14(3):361–368.
   PubMed Web of Science ®Google Scholar
• Riching KM, Mahan S, Corona CR, et al. Quantitative live-cell kinetic degradation and mechanistic profiling of PROTAC mode of action. ACS Chem Biol. 2018;13(9):2758–2770.
   PubMed Web of Science ®Google Scholar
• Maniaci C, Hughes SJ, Testa A, et al. Homo-PROTACs: bivalent small molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation. Nat Commun. 2017;8(1):830.
   PubMedGoogle Scholar
• Steinebach C, Lindner S, Udeshi ND, et al. Homo-PROTACs for the chemical knockdown of cereblon. ACS Chem Biol. 2018;13(9):2771–2782.
   PubMed Web of Science ®Google Scholar
• Girardini M, Maniaci C, Hughes SJ, et al. cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs. Bioorg Med Chem. 2019;pii: S0968-0896(19):30172–30175.
   Google Scholar
• Steinebach C, Kehm H, Lindner S, et al. PROTAC-mediated crosstalk between E3 ligases. Chem Commun. 2019;55(12):1821–1824.
   PubMed Web of Science ®Google Scholar
• Li Y, Yang J, Aguilar A, et al. 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. 2019;62(2):448–466.
   PubMed Web of Science ®Google Scholar
• Chu TT, Gao N, Li QQ, et al. Specific knockdown of endogenous Tau protein by peptide-directed ubiquitin-proteasome degradation. Cell Chem Biol. 2016;23(4):453–461.
   PubMed Web of Science ®Google Scholar
• Lu M, Liu T, Jiao Q, et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur J Med Chem. 2018;146:251–259.
   PubMed Web of Science ®Google Scholar
• Silva MC, Ferguson FM, Cai Q, et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. ELIFE. 2019;8:e45457.
   PubMed Web of Science ®Google Scholar
• Kargbo RB. Treatment of Alzheimer’s by PROTAC-Tau protein degradation. ACS Med Chem Lett. 2019;10(5):699–700.
   PubMedGoogle Scholar
• Kenten JH, Roberts SF, (PROTEINEX INC). Controlling protein levels in eucaryotic organisms. US6306663B1 (1999).
   Google Scholar
• a) http://arvinas.com/wp-content/uploads/2018/02/AR-GUASCO2018-final.pdf, b) Neklesa T, Snyder LB, Willard RR et al. ARV-110: an oral androgen receptor PROTAC degrader for prostate cancer. J Clin Oncol. 2019; 37(7)_suppl:259-259. DOI: https://doi.org/10.1200/JCO.2019.37.7_suppl.259.
   Google Scholar
• Salami J, Alabi S, Willard RR, et al. Androgen receptor degradation by the proteolysis targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun Biol. 2018;1:100.
   PubMed Web of Science ®Google Scholar
• Chan KH, Zengerle M, Testa A, et al. Impact of target warhead and linkage vector on inducing protein degradation: comparison of bromodomain an extra-terminal (BET) degraders derived from thiazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds. J Med Chem. 2018;61(2):504–513.
   PubMed Web of Science ®Google Scholar
• McCoull W, Cheung T, Anderson E, et al. Development of a novel B-cell lymphoma 6 (BCL6) PROTAC to provide insight into small molecule targeting of BCL6. ACS Chem Biol. 2018;13(11):3131–3141.
   PubMed Web of Science ®Google Scholar
• Cromm PM, Samarasinghe KTG, Hines J, et al. Addressing kinase-independent functions of Fak via PROTAC-mediated degradation. J Am Chem Soc. 2018;140(49):17019–17026.
   PubMed Web of Science ®Google Scholar
• Zhang L, Rilery-Gillis B, Vijay P, et al. Acquired resistance to BET-PROTACs (proteolysis targeting chimeras) caused by genomic alterations in core components of E3 ligase complexes. Mol Cancer Ther. 2019;pii: molcanther:1129. 2018.
   Google Scholar
• Chen Z, Picaud S, Filippakopoulos, et al. Structural basis for recruitment of DAPK1 to the KLHL20 E3 ligase. DOI:https://doi.org/10.1101/414250.
   Google Scholar
• Sievers QL, Petzold G, Bunker RD, et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science. 2018;362(6414):pii: eaat0572.
   PubMed Web of Science ®Google Scholar
• Guo J, Liu J, Wei W. Degrading proteins in animals: “PROTAC”tion goes in vivo. Cell Res. 2019;29:179–180.
   PubMed Web of Science ®Google Scholar
• Nalawansha DA, Paiva S-L, Rafizadeh DN, et al. Targeted protein internalization and degradation by ENDosome Targeting Chimeras (ENDTACs). ACS Cent Sci. 2019; 5:1079–1084 article ASAP.
   PubMed Web of Science ®Google Scholar