Novel approaches to targeted protein degradation technologies in drug discovery

References

• Dikic I. Proteasomal and autophagic degradation systems. Annu Rev Biochem. 2017 Jun;86(1):193–224.
   PubMedGoogle Scholar
• Lilienbaum A. Relationship between the proteasomal system and autophagy. Int J Biochem Mol Biol. 2013;4(1):1–26.
   PubMedGoogle Scholar
• Tan X, Calderon-Villalobos LI, Sharon M, et al. Mechanism of auxin perception by the TIR1 ubiquitin ligase. Nature. 2007 Apr 5;446(7136):640–645.
   PubMed Web of Science ®Google Scholar
• Sheard LB, Tan X, Mao H, et al. Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ co-receptor. Nature. 2010 Nov 18;468(7322):400–405.
   PubMed Web of Science ®Google Scholar
• Murase K, Hirano Y, Sun TP, et al. Gibberellin-induced DELLA recognition by the gibberellin receptor GID1. Nature. 2008 Nov 27;456(7221):459–463.
   PubMedGoogle Scholar
• Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010 Mar 12;327(5971):1345–1350.
   PubMed Web of Science ®Google Scholar
• Zhu YX, Braggio E, Shi C-X, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011 Nov 03;118(18):4771–4779.
   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 Nov 01;26(11):2326–2335.
   PubMed Web of Science ®Google Scholar
• 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 U S A. 2001 Jul 17;98(15):8554–8559.
   PubMed Web of Science ®Google Scholar
• Yang J, Li Y, 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 Med Chem. 2019 Nov 14;62(21):9471–9487.
   PubMed Web of Science ®Google Scholar
• Furuya N, Momose T, Katsuno K, et al. An isoform-selective inhibitor of tropomyosin receptor kinase A behaves as molecular glue. Bioorg Med Chem Lett. 2020 Jan 1;30(1):126775.
   PubMedGoogle Scholar
• St-Cyr D, Ceccarelli DF, Orlicky S, et al. Identification and optimization of molecular glue compounds that inhibit a noncovalent E2 enzyme-ubiquitin complex. Sci Adv. 2021 Oct 29;7(44):eabi5797.
   PubMedGoogle Scholar
• Liu J, Farmer JD Jr., Lane WS, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807–815.
   PubMed Web of Science ®Google Scholar
• Moon J, Parry G, Estelle M. The ubiquitin-proteasome pathway and plant development. Plant Cell. 2004 Dec;16(12):3181–3195.
   PubMedGoogle Scholar
• Dharmasiri N, Estelle M. Auxin signaling and regulated protein degradation. Trends Plant Sci. 2004 Jun;9(6):302–308.
   PubMedGoogle Scholar
• Thines B, Katsir L, Melotto M, et al. JAZ repressor proteins are targets of the SCF(COI1) complex during jasmonate signalling. Nature. 2007 Aug 9;448(7154):661–665.
   PubMed Web of Science ®Google Scholar
• Sun TP. Gibberellin-GID1-DELLA: a pivotal regulatory module for plant growth and development. Plant Physiol. 2010 Oct;154(2):567–570.
   PubMed Web of Science ®Google Scholar
• Nishimura K, Fukagawa T, Takisawa H, et al. An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat Methods. 2009 Dec;6(12):917–922.
   PubMed Web of Science ®Google Scholar
• Miller MT, Stromland K. Teratogen update: thalidomide: a review, with a focus on ocular findings and new potential uses. Teratology. 1999 Nov;60(5):306–321.
   PubMedGoogle Scholar
• Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014 Jan 17;343(6168):301–305.
   PubMed Web of Science ®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 Nov 2;362(6414):eaat0572.
   PubMed Web of Science ®Google Scholar
• Kronke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature. 2015 Jul 9;523(7559):183–188.
   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 Jul 14;535(7611):252–257.
   PubMed Web of Science ®Google Scholar
• Hansen JD, Correa M, Alexander M, et al. CC-90009: a cereblon E3 ligase modulating drug that promotes selective degradation of GSPT1 for the treatment of acute myeloid leukemia. J Med Chem. 2021 Feb 25;64(4):1835–1843.
   PubMed Web of Science ®Google Scholar
• Wang ES, Verano AL, Nowak RP, et al. Acute pharmacological degradation of Helios destabilizes regulatory T cells. Nat Chem Biol. 2021 Jun;17(6):711–717.
   PubMedGoogle Scholar
• Koduri V, Duplaquet L, Lampson BL, et al. Targeting oncoproteins with a positive selection assay for protein degraders. Sci Adv. 2021 Feb;7(6):eabd6263.
   PubMedGoogle Scholar
• Kaelin WG Jr. Common pitfalls in preclinical cancer target validation. Nat Rev Cancer. 2017 Jul;17(7):425–440.
   PubMed Web of Science ®Google Scholar
• Ishoey M, Chorn S, Singh N, et al. Translation termination factor GSPT1 is a phenotypically relevant off-target of heterobifunctional phthalimide degraders. ACS Chem Biol. 2018 Mar 16;13(3):553–560.
   PubMed Web of Science ®Google Scholar
• Huber AD, Li Y, Lin W, et al. SJPYT-195: a designed nuclear receptor degrader that functions as a molecular glue degrader of GSPT1. ACS Med Chem Lett. 2022 Aug 11;13(8):1311–1320.
   PubMedGoogle Scholar
• Yang Z, Sun Y, Ni Z, et al. Merging PROTAC and molecular glue for degrading BTK and GSPT1 proteins concurrently. Cell Res. 2021 Dec;31(12):1315–1318.
   PubMedGoogle Scholar
• Ozawa Y, Kusano K, Owa T, et al. Therapeutic potential and molecular mechanism of a novel sulfonamide anticancer drug, indisulam (E7070) in combination with CPT-11 for cancer treatment. Cancer Chemother Pharmacol. 2012 May;69(5):1353–1362.
   PubMedGoogle Scholar
• Han T, Goralski M, Gaskill N, et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science. 2017 Apr 28;356:6336.
   Web of Science ®Google Scholar
• Uehara T, Minoshima Y, Sagane K, et al. Selective degradation of splicing factor CAPERalpha by anticancer sulfonamides. Nat Chem Biol. 2017 Jun;13(6):675–680.
   PubMed Web of Science ®Google Scholar
• Ting TC, Goralski M, Klein K, et al. Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15. Cell Rep. 2019 Nov 5;29(6):1499–1510 e6.
   PubMedGoogle Scholar
• Bussiere DE, Xie L, Srinivas H, et al. Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat Chem Biol. 2020 Jan;16(1):15–23.
   PubMed Web of Science ®Google Scholar
• Faust TB, Yoon H, Nowak RP, et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat Chem Biol. 2020 Jan;16(1):7–14.
   PubMed Web of Science ®Google Scholar
• Mayor-Ruiz C, Bauer S, Brand M, et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat Chem Biol. 2020 Nov;16(11):1199–1207.
   PubMed Web of Science ®Google Scholar
• Fu T-J, Peng J, Lee G, et al. Cyclin K Functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription*. J Biol Chem. 1999 Dec 03;274(49):34527–34530.
   PubMed Web of Science ®Google Scholar
• Slabicki M, Kozicka Z, Petzold G, et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature. 2020 Sep;585(7824):293–297.
   PubMed Web of Science ®Google Scholar
• Lv L, Chen P, Cao L, et al. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. Elife. 2020 Aug 17;9:e59994.
   PubMed Web of Science ®Google Scholar
• Dieter SM, Siegl C, Codo PL, et al. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell Rep. 2021 Jul 20;36(3):109394.
   PubMed Web of Science ®Google Scholar
• Kerres N, Steurer S, Schlager S, et al. Chemically induced degradation of the oncogenic transcription factor BCL6. Cell Rep. 2017 Sep 19;20(12):2860–2875.
   PubMed Web of Science ®Google Scholar
• Slabicki M, Yoon H, Koeppel J, et al. Small-molecule-induced polymerization triggers degradation of BCL6. Nature. 2020 Dec;588(7836):164–168.
   PubMedGoogle Scholar
• Toriki ES, Papatzimas JW, Nishikawa K, et al. Rational chemical design of molecular glue degraders. bioRxiv. 2022 Nov 04;512693 https://doi.org/10.1101/2022.11.04.512693.
   Google Scholar
• Liu TT, Yang H, Zhuo FF, et al. Atypical E3 ligase ZFP91 promotes small-molecule-induced E2F2 transcription factor degradation for cancer therapy. EBioMedicine. 2022;Dec 86 104353.
   PubMedGoogle Scholar
• Wang P, Zhou J. Proteolysis targeting chimera (PROTAC): a paradigm-shifting approach in small molecule drug discovery. Curr Top Med Chem. 2018;18(16):1354–1356.
   PubMed Web of Science ®Google Scholar
• Li D, Yu D, Li Y, et al. A bibliometric analysis of PROTAC from 2001 to 2021. Eur J Med Chem. 2022 Oct 14;244:114838.
   PubMedGoogle Scholar
• He M, Cao C, Ni Z, et al. PROTACs: great opportunities for academia and industry (an update from 2020 to 2021). Signal Transduct Target Ther. 2022 Jun 9;7(1):181.
   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 Apr 28;132(16):5820–5826.
   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 Mar 25;8:e45457.
   PubMed Web of Science ®Google Scholar
• Zheng M, Huo J, Gu X, et al. Rational design and synthesis of novel dual PROTACs for simultaneous degradation of EGFR and PARP. J Med Chem. 2021 Jun 10;64(11):7839–7852.
   PubMed Web of Science ®Google Scholar
• Pal P, Thummuri D, Lv D, et al. Discovery of a novel BCL-X(L) PROTAC degrader with enhanced BCL-2 inhibition. J Med Chem. 2021 Oct 14;64(19):14230–14246.
   PubMed Web of Science ®Google Scholar
• Lv D, Pal P, Liu X, et al. Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity. Nat Commun. 2021 Nov 25;12(1):6896.
   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 Nov 16;13(11):3131–3141.
   PubMed Web of Science ®Google Scholar
• Roatsch M, Vogelmann A, Herp D, et al. Proteolysis-Targeting Chimeras (PROTACs) Based on Macrocyclic Tetrapeptides Selectively Degrade Class I Histone Deacetylases 1-3. ChemRxiv. 2020 Jun 4;12416303 http://doi.org/10.26434/chemrxiv.12416303.v1.
   Google Scholar
• Testa A, Hughes SJ, Lucas X, et al. Structure-Based Design of a Macrocyclic PROTAC. Angew Chem Int Ed Engl. 2020 Jan 20;59(4):1727–1734.
   PubMed Web of Science ®Google Scholar
• Pfaff P, Samarasinghe KTG, Crews CM, et al. Reversible spatiotemporal control of induced protein degradation by bistable photoprotacs. ACS Cent Sci. 2019 Oct 23;5(10):1682–1690.
   PubMed Web of Science ®Google Scholar
• Jin YH, Lu MC, Wang Y, et al. Azo-PROTAC: novel light-controlled small-molecule tool for protein knockdown. J Med Chem. 2020 May 14;63(9):4644–4654.
   PubMed Web of Science ®Google Scholar
• Reynders M, Matsuura BS, Berouti M, et al. PHOTACs enable optical control of protein degradation. Sci Adv. 2020 Feb;6(8):eaay5064.
   PubMed Web of Science ®Google Scholar
• Xue G, Wang K, Zhou D, et al. Light-Induced Protein degradation with photocaged PROTACs. J Am Chem Soc. 2019 Nov 20;141(46):18370–18374.
   PubMed Web of Science ®Google Scholar
• Liu J, Chen H, Ma L, et al. Light-induced control of protein destruction by opto-PROTAC. Sci Adv. 2020 Feb;6(8):eaay5154.
   PubMed Web of Science ®Google Scholar
• Naro Y, Darrah K, Deiters A. Optical Control of Small Molecule-induced protein degradation. J Am Chem Soc. 2020 Feb 5;142(5):2193–2197.
   PubMed Web of Science ®Google Scholar
• Kim JW, Gao P, Dang CV. Effects of hypoxia on tumor metabolism. Cancer Metastasis Rev. 2007 Jun;26(2):291–298.
   PubMed Web of Science ®Google Scholar
• Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010 May;44(5):479–496.
   PubMed Web of Science ®Google Scholar
• Shi S, Du Y, Zou Y, et al. Rational design for nitroreductase (NTR)-responsive proteolysis targeting chimeras (PROTACs) selectively targeting tumor tissues. J Med Chem. 2022 Mar 24;65(6):5057–5071.
   PubMedGoogle Scholar
• Liu H, Ren C, Sun R, et al. Reactive oxygen species-responsive Pre-PROTAC for tumor-specific protein degradation. Chem Commun (Camb). 2022 Sep 8;58(72):10072–10075.
   PubMedGoogle Scholar
• Zhang S, Li Y, Li T, et al. Activable targeted protein degradation platform based on light-triggered singlet oxygen. J Med Chem. 2022 Feb 24;65(4):3632–3643.
   PubMedGoogle Scholar
• Pillow TH, Adhikari P, Blake RA, et al. Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity. ChemMedChem. 2020 Jan 7;15(1):17–25.
   PubMedGoogle Scholar
• Dragovich PS, Pillow TH, Blake RA, et al. Antibody-mediated delivery of chimeric BRD4 degraders. Part 1: exploration of antibody linker, payload loading, and payload molecular properties. J Med Chem. 2021 Mar 11;64(5):2534–2575.
   PubMedGoogle Scholar
• Dragovich PS, Pillow TH, Blake RA, et al., Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of in vitro Antiproliferation Activity and in vivo Antitumor Efficacy. J Med Chem. 2021 Mar 11;64(5):2576–2607.
   PubMedGoogle Scholar
• Dragovich PS, Adhikari P, Blake RA, et al. Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERalpha). Bioorg Med Chem Lett. 2020 Feb 15;30(4):126907.
   PubMedGoogle Scholar
• Maneiro MA, Forte N, Shchepinova MM, et al. Antibody-PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4. ACS Chem Biol. 2020 Jun 19;15(6):1306–1312.
   PubMedGoogle Scholar
• Qu J, Ren X, Xue F, et al. Specific Knockdown of alpha-Synuclein by Peptide-Directed Proteasome Degradation Rescued Its Associated Neurotoxicity. Cell Chem Biol. 2020 Jun 18;27(6):751–762 e4.
   PubMed Web of Science ®Google Scholar
• Jiang Y, Deng Q, Zhao H, et al. Development of stabilized peptide-based PROTACs against estrogen receptor alpha. ACS Chem Biol. 2018 Mar 16;13(3):628–635.
   PubMedGoogle Scholar
• Chen S, Li X, Li Y, et al. Design of stapled peptide-based PROTACs for MDM2/MDMX atypical degradation and tumor suppression [Research Paper]. Theranostics. 2022;12(15):6665–6681.
   Google Scholar
• Ghidini A, Clery A, Halloy F, et al. RNA-PROTACs: degraders of RNA-binding proteins. Angew Chem Int Ed Engl. 2021 Feb 8;60(6):3163–3169.
   PubMed Web of Science ®Google Scholar
• Naganuma M, Ohoka N, Tsuji G, et al. Development of chimeric molecules that degrade the estrogen receptor using decoy oligonucleotide ligands. ACS Med Chem Lett. 2022 Jan 13;13(1):134–139.
   PubMedGoogle Scholar
• Samarasinghe KTG, An E, Genuth MA, et al. OligoTRAFTACs: a generalizable method for transcription factor degradation. RSC Chem Biol. 2022 Aug 31;3(9):1144–1153.
   PubMedGoogle Scholar
• Zhang L, Li L, Wang X, et al. Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin. Mol Ther Nucleic Acids. 2022 Dec;13(30):66–79.
   Google Scholar
• Burslem GM, Crews CM. Small-molecule modulation of protein homeostasis. Chem Rev. 2017 Sep 13;117(17):11269–11301.
   PubMed Web of Science ®Google Scholar
• Banik SM, Pedram K, Wisnovsky S, et al. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature. 2020 Aug;584(7820):291–297.
   PubMed Web of Science ®Google Scholar
• Ahn G, Banik SM, Miller CL, et al. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Biol. 2021 Sep;17(9):937–946.
   PubMedGoogle Scholar
• Zhou Y, Teng P, Montgomery NT, et al. Development of Triantennary N-Acetylgalactosamine conjugates as degraders for extracellular proteins. ACS Cent Sci. 2021 Mar 24;7(3):499–506.
   PubMedGoogle Scholar
• Caianiello DF, Zhang M, Ray JD, et al. Bifunctional small molecules that mediate the degradation of extracellular proteins. Nat Chem Biol. 2021 Sep;17(9):947–953.
   PubMedGoogle Scholar
• Takahashi D, Moriyama J, Nakamura T, et al. AUTACs: cargo-specific degraders using selective autophagy. Mol Cell. 2019 Dec 5;76(5):797–810 e10.
   PubMed Web of Science ®Google Scholar
• Pei J, Pan X, Wang A, et al. Developing potent LC3-targeting AUTAC tools for protein degradation with selective autophagy. Chem Commun (Camb). 2021 Dec 7;57(97):13194–13197.
   PubMedGoogle Scholar
• Ji CH, Kim HY, Lee MJ, et al. The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system. Nat Commun. 2022 Feb 16;13(1):904.
   PubMed Web of Science ®Google Scholar
• Li Z, Wang C, Wang Z, et al. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature. 2019 Nov;575(7781):203–209.
   PubMed Web of Science ®Google Scholar
• Li Z, Zhu C, Ding Y, et al. ATTEC: a potential new approach to target proteinopathies. Autophagy. 2020 Jan;16(1):185–187.
   PubMedGoogle Scholar
• Fu Y, Chen N, Wang Z, et al. Degradation of lipid droplets by chimeric autophagy-tethering compounds. Cell Res. 2021 Sep;31(9):965–979.
   PubMed Web of Science ®Google Scholar
• Dong G, Wu Y, Cheng J, et al. Ispinesib as an effective warhead for the design of autophagosome-tethering chimeras: discovery of potent degraders of nicotinamide phosphoribosyltransferase (NAMPT). J Med Chem. 2022 Jun 9;65(11):7619–7628.
   PubMedGoogle Scholar
• Yang C, Yang Y, Li Y, et al. Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors. J Am Chem Soc. 2023 Jan;145(1):385–391.
   PubMedGoogle Scholar
• Pei J, Xiao Y, Liu X, et al. Piperlongumine conjugates induce targeted protein degradation. Cell Chem Biol. 2023 Feb 16;30(2): 203–213.e17.
   PubMedGoogle Scholar
• Imaide S, Riching KM, Makukhin N, et al. Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity. Nat Chem Biol. 2021 Nov;17(11):1157–1167.
   PubMed Web of Science ®Google Scholar
• Sosic I, Bricelj A, Steinebach C. E3 ligase ligand chemistries: from building blocks to protein degraders. Chem Soc Rev. 2022 May 10; 51(9):3487–3534.
   PubMedGoogle Scholar
• Morreale FE, Kleine S, Leodolter J, et al. BacPROTACs mediate targeted protein degradation in bacteria. Cell. 2022 Jun 23;185(13):2338–2353 e18.
   PubMed Web of Science ®Google Scholar
• Cheng J, He S, Xu J, et al. Making protein degradation visible: discovery of theranostic PROTACs for detecting and degrading NAMPT. J Med Chem. 2022 Dec 8;65(23):15725–15737.
   PubMedGoogle Scholar
• Henning NJ, Boike L, Spradlin JN, et al. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat Chem Biol. 2022 Apr;18(4):412–421.
   PubMedGoogle Scholar
• Raina K, Forbes CD, Stronk R, et al. Regulated induced proximity targeting chimeras (RIPTACs): a novel heterobifunctional small molecule therapeutic strategy for killing cancer cells selectively. bioRxiv. 2023 Jan 2;2023(1.01):522436.
   Google Scholar
• Zhou YF, Wang J, Deng MF, et al. The peptide-directed lysosomal degradation of CDK5 exerts therapeutic effects against stroke. Aging Dis. 2019;Oct;10(5):1140–1145.
   PubMedGoogle Scholar