Research Progress in Proteolysis Targeting Chimeras Based on Small Molecule E3 Ubiquitin Ligase Adaptor
LIU Bin1,2, ZHU Zhou-jing1, TONG Hong-juan1, ZHANG Yan-min2, TANG Chu3
1. School of Pharmacy, Shaanxi Institute of International Trade and Commerce, Xianyang 712046, China; 2. Collaborative Innovation Center of Green Manufacturing Technology for Traditional Chinese Medicine in Shaanxi Province, Xianyang 712046, China; 3. School of Life Science and Technology, Xidian University, Xi'an 710126, China
Abstract：Proteolysis targeting chimeras (PROTACs) is a class of bifunctional molecules that recruit target proteins and induce their ubiquitination and degradation. Compared with traditional small molecule inhibitors, the mode of action of PROTACs that directly degrades the target protein has high selectivity and efficiency. More importantly, the technology can target non-druggable proteins and solve the problems of small molecule drug resistance. E3 ubiquitin ligase participates in the degradation pathway of the ubiquitin proteasome system, and determines the specific recognition of the PROTACs molecule targeting E3 ubiquitin ligase. The huge E3 family is crucial to the development of PROTACs technology. Compared with the first-generation peptide PROTACs, the second-generation small molecule PROTACs have better transmembrane properties, stability and druggability. This review mainly introduces the mechanism of action of PROTACs based on the design of small molecule E3 ligase, the latest research results, and the current problems.
LAI A C, CREWS C M. Induced protein degradation: An emerging drug discovery paradigm[J]. Nat Rev Drug Discov, 2017, 16(2): 101-114.
[2]
SALAMI J, CREWS C M. Waste disposal-an attractive strategy for cancer therapy[J]. Science, 2017, 355(6330):1163-1167.
[3]
BERNASSOLA F, KARIN M, CIECHANOBERE A, et al. The HECT family of E3 ubiquitin ligases: multiple players in cancer development[J]. Cancer Cell, 2008, 14(1): 10-21.
[4]
DESHAIES R J, JOAZEIRO C A P. RING domain E3 ubiquitin ligases[J]. Annu Rev Biochem, 2009, 78: 399-434
[5]
MSRSH D J, DICHSON K A. Writing histone monoubiquitination in human malignancy-The role of ring finger E3 ubiquitin ligases[J]. Genes, 2019, 10(1): 67. doi:10.3390/genes10010067.
[6]
SAKANOTO K M, KIM K B, KUMAGAI A, et al. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation[J]. Proc Natl Acad Sci USA, 2001, 98(15): 8554-8559.
[7]
SAKANOTO K M. Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation[J]. Mol Cell Proteom, 2004, 2(12): 1350-1358.
[8]
YUKIHIRO I, MINORU I, MIKIHIKO N, 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]. J Am Chem Soc, 2010, 132(16): 5820-5826.
[9]
WANG Z, LIU P, INUZULA H, et al. Roles of F-box proteins in cancer[J]. Nat Rev Cancer, 2014, 14(4): 233-247.
[10]
CIECHANOVER A. The unravelling of the ubiquitin system[J]. Nat Rev Mol Cell Biol, 2015, 16(5): 322-324.
[11]
SCHNEEKLOTH A R, PUCHEAULT M, TAE H S. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics[J]. Bioorg Med Chem Lett, 2008, 18(22): 5904-5908.
[12]
WINTER G E, BUCKLEY D L, PAULK J, et al. Drug development Phthalimide conjugation as a strategy for in vivo target protein degradation[J]. Science, 2015, 348(6241): 1376-1381.
[13]
GADD M S, TESTA A, LUCAS X, et al. Structural basis of PROTAC cooperative recognition for selective protein degradation[J]. Nat Chem Biol, 2017, 13(5): 514-521.
[14]
LU J, QIAN Y, ALTIERI M, et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4[J]. Chem Biol, 2015, 22(6): 755-763.
[15]
VECINO R, BURGUETE M C, JOVER-MENGUAL T, et al. The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia[J]. Sci Rep, 2018, 8(1): 1610. doi:10.1038/s41598-018-19921-x.
[16]
HINES J, LARTIGUE S, DONG H Q, et al. MDM2-recruiting PROTAC offers superior, synergistic anti-proliferative activity via simultaneous degradation of BRD4 and stabilization of p53[J]. Cancer Res, 2019, 79(1): 251-262.
[17]
LI Y B, AGUILAR J L, MCEACHERN 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]. J Med Chem, 2019, 62(2): 448-466.
[18]
ITO H, ANDO T, SUZUKI T, et al. Identification of a primary target of thalidomide teratogenicity[J]. Science, 2010, 327(5971): 1345-1350.
[19]
KRONKE J, UDESHI N D, NARLA N, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells[J]. Science, 2014, 343(6168): 301-305.
[20]
YANG J L, LI Y B, AGUILAR A, et al. Simple structural modifications converting a bona fide MDM2 PROTAC degrader into a molecular glue molecule: A cautionary tale in the design of PROTAC degraders[J]. J Med Chem, 2019, 62(21): 9471-9487.
[21]
BARTHOLOMEEUSEN K, XIANG Y, FUJINAGA K, et al. Bromodomain and extra-terminal (BET) bromodomain inhibition activate transcription via transient release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein[J]. J Biol Chem, 2012, 287(43): 36609-36616.
[22]
NICODEME E, JEFFREY K L, SCHAEFER U, et al. Suppression of inflammation by a synthetic histone mimic[J]. Nature, 2010, 468(7327): 1119-1123.
[23]
ZUBER J, SHI J S, WANG E, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia[J]. Nature, 2011, 478(7370):524-528.
[24]
YANG C Y, QIN C, BAI L S, et al. Small-molecule PROTAC degraders of the bromodomain and extra terminal (BET) proteins-a review[J]. Drug Discov Today Technol, 2019, 31: 43-51.
[25]
QIN C, HU Y, ZHOU B, et al. Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression[J]. J Med Chem, 2018, 61(15): 6685-6704.
[26]
ZHOU B, HU J T, XU F M, 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]. J Med Chem, 2018, 61(2): 462-481.
[27]
LIU J, CHEN H, MA L N, et al. Light-induced control of protein destruction by opto-PROTAC[J]. Sci Adv, 2020, 6(8): eaay5154. doi:10.1126/sciadv.aay5154.
[28]
BACON C W, ORSO D I. CDK9: A signaling hub for transcriptional control[J]. Transcription, 2019, 10(2):57-75.
[29]
ROBB C M, CONTRERAS J I, KOUR S, et al. Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)[J]. Chem Commun (Camb), 2017, 53(54):7577-7580.
[30]
BIAN J L, REN J, LI Y R, et al. Discovery of Wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity[J]. Bioorg Chem, 2018, 81: 373-381.
[31]
OLSON C M, JIANG B S, ERB M A, et al. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation[J]. Nat Chem Biol, 2018, 14(2):163-170.
[32]
JIANG B S, WANG E S, DONOVAN K, et al. Development of dual and selective degraders of cyclin-dependent kinases 4 and 6[J]. Angew Chem Int Ed Engl, 2019, 58(19): 6321-6326.
[33]
BRAND M, JIANG B S, BAUER S, et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML[J]. Cell Chem Biol, 2019, 26(2): 300-306.
[34]
SILVA M C, FERGUSON F M, CAI Q, et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models[J]. eLife Sci, 2019, 8:e45457. doi: 10.7554/eLife.45457.
[35]
ZENG M, XIONG Y, SAFAEE N, et al. Exploring targeted degradation strategy for oncogenic KRASG12C[J]. Cell Chem Biol, 2020, 27(1):19-31.
[36]
BUCKLEY D L, GUSTAFSON J L, MOLLE I V, et al. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha[J]. Angew Chem Int Ed Engl, 2012, 51(46):11463-11467.
[37]
BONDESON D P, MARES A, SMITH I E, et al. Catalytic in vivo protein knockdown by small molecule PROTACs[J]. Nat Chem Biol, 2015, 11(8): 611-617.
[38]
BURSLEM G M, SMITH B E, LAI A C, et al. The advantages of targeted protein degradation over inhibition: An RTK case study[J]. Cell Chem Biol, 2018, 25(1): 67-77.
[39]
ALABI S, JAIME-FIGUEROA S, YAO Z, et al. Mutant-selective degradation by BRAF-targeting PROTACs[J]. Nat Commun, 2021, 12(1): doi:10.1038/s41467-021-21159-7.
[40]
ZHAO Q J, REN C W, LIU L Y, et al. Discovery of SIAIS178 as an effective BCR-ABL degrader by recruiting von hippel-lindau (VHL) E3 ubiquitin ligase[J]. J Med Chem, 2019, 62(20): 9281-9298.
[41]
TOVELL H, TESTA A, ZHOU H J, et al. Design and characterization of SGK3-PROTAC1, an isoform specific SGK3 kinase PROTAC degrader[J]. ACS Chem Biol, 2019, 14(9): 2024-2034.
[42]
FARNABY W, KOEGL M, ROY M J, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design[J]. Nat Chem Biol, 2019, 15(7): 672-680.
[43]
ZOPPI V, HUGHES S J, MANIACI C, et al. 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]. J Med Chem, 2019, 62(2): 699-726.
[44]
CROMM P M, SAMARASINGHE K, HINES J, et al. Addressing kinase independent functions of fak via PROTAC-mediated degradation[J]. J Am Chem Soc, 2018, 140(49): 17019-17026.
[45]
HU J T, HU B, WANG M L, et al. Discovery of ERD-308 as a highly potent proteolysis targeting chimera (PROTAC) degrader of estrogen receptor (ER)[J]. J Med Chem, 2019, 62(3): 1420-1442.
[46]
ZHENG M Z, HUO J F, GU X X, et al. Rational design and synthesis of novel dual protacs for simultaneous degradation of EGFR and PARP[J]. J Med Chem, 2021, 64(11): 7839-7852.
[47]
CONG H, XU L J, WU Y G, et al. Inhibitor of apoptosis protein (IAP) antagonists in anticancer agent discovery: Current status and perspectives[J]. J Med Chem, 2019, 62(12): 5750-5772.
[48]
YANG L L, BHAVAN K, SHEN C X, et al. LCL161, a SMAC mimetic, preferentially radiosensitizes human papillomavirus negative head and neck squamous cell carcinoma[J]. Mol Cancer Ther, 2019, 18(6):1025-1035.
[49]
NAITO M, OHOKA N, SHIBATA N. SNIPERs-hijacking IAP activity to induce protein degradation[J]. Drug Discov Today Technol, 2019, 31: 35-42. doi: 10.1016/j.ddetc.2018.12.002.
[50]
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[J]. Biorg Med Chem Lett, 2012, 22(13): 4453-4457.
[51]
OKUHIRA K, SHODA T, OMURA R, et al. Targeted degradation of proteins localized in subcellular compartments by hybrid small molecules[J]. Mol Pharmacol, 2017, 91(3): 159-166.
[52]
OHOKA N, MORITA Y, NAGAI K, et al. Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation[J]. J Biol Chem, 2018, 293(18): 6776-6790.
[53]
SHIMOKAWA K, SHIBATA N, SAMESHIMA T, et al. Targeting the allosteric site of oncoprotein BCR-ABL as an alternative strategy for effective target protein degradation[J]. ACS Med Chem Lett, 2017, 8(10): 1042-1047.
[54]
OHOKA N, UJIKAWA O, SHIMOKAWA K, et al. Different degradation mechanisms of inhibitor of apoptosis proteins (IAPs) by the specific and nongenetic IAP-dependent protein eraser (SNIPER)[J]. Chem Pharm Bull, 2019, 67(3): 203-209.
[55]
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]. J Biol Chem, 2017, 292(11): 4556-4570.
[56]
OHOKA N, MORITA Y, NAGAI K, et al. Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor alpha degradation[J]. J Biol Chem, 2018, 293(18): 6776-6790.
[57]
LIU L H, DAMERELL D R, LEONIDAS K, et al. UbiHub: a data hub for the explorers of ubiquitination pathways[J]. Bioinformatics, 2019, 35(16): 2882-2884.
[58]
ZHANG X Y, CROWLEY V M, WUCHERPFENNIG T G, et al. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16 [J]. Nat Chem Biol, 2019, 15(7):737-746.
[59]
HAN T, CORALSHI M, GASKILL N, et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15[J]. Science, 2017, 356(6336): eaal3755.
[60]
ZHANG X Y, LUUKKONEN L M, EISSLER C L, et al. DCAF11 supports targeted protein degradation by electrophilic proteolysis-targeting chimeras[J]. J Am Chem Soc, 2021, 143(13):5141-5149.
[61]
SMITH B E, WANG S L, JAIMF-FIGUEROA S, et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase[J]. Nat Commun, 2019, 10(1): 131. doi: 10.1038/s41467-018-08027-7.
[62]
NAWAK R P, STEPHEN L D, BUCKLEY D, et al. Plasticity in binding confers selectivity in ligand-induced protein degradation[J]. Nat Chem Biol, 2018, 14(7):706-714.
[63]
HAN X, ZHAO L J, XIANG W G, et al. Strategies toward discovery of potent and orally bioavailable proteolysis targeting chimera degraders of androgen receptor for the treatment of prostate cancer [J]. J Med Chem, 2021, 64(17):12831-12854.
2022, Vol. 57 
