Photocontrollable PROTAC molecules – structure and mechanism of action
Abstract
Traditional drug discovery strategies are usually focused on occupancy of binding sites that directly affect functions of proteins. Hence, proteins that lack such binding sites are generally considered pharmacologically intractable. Modulators of protein activity, especially inhibitors, must be applied in appropriate dosage regimens that often lead to high systemic drug exposures in order to maintain sufficient protein inhibition in vivo. Consequently, there is a risk of undesirable off-target drug binding and side effects. Recently, PROteolysis TArgeting Chimera (PROTAC) technology has emerged as a new pharmacological modality that exploits PROTAC molecules for induced protein degradation. PROTAC molecule is a heterobifunctional structure consisting of a ligand that binds a protein of interest (POI), a ligand for recruiting an E3 ubiquitin ligase (an enzyme involved in the POI ubiquitination) and a linker that connects these two. After POI-PROTAC-E3 ubiquitin ligase ternary complex formation, the POI undergoes ubiquitination (an enzymatic post-translational modification in which ubiquitin is attached to the POI) and degradation. By merging the principles of photopharmacology and PROTAC technology, photocontrollable PROTACs for spatiotemporal control of induced protein degradation have recently emerged. The main advantage of photocontrollable over conventional PROTACs is the possible prevention of off-target toxicity thanks to local photoactivation.
References
Campbell J, Ryan CJ, Brough R, Bajrami I, Pemberton HN, Chong IY, et al. Large- scale profiling of kinase dependencies in cancer cell lines. Cell Rep. 2016;14(10):2490- 501.
Cowley GS, Weir BA, Vazquez F, Tamayo P, Scott JA, Rusin S, et al. Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies. Sci Data. doi: 10.1038/sdata.2014.35.
Wang T, Birsoy K, Hughes NW, Krupczak KM, Post Y, Wei JJ, et al. Identification and characterization of essential genes in the human genome. Science. 2015;350(6264):1096-101.
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603-7.
Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov. 2002;1(9):727-30.
Lazo JS, Sharlow ER. Drugging undruggable molecular cancer targets. Annu Rev Pharmacol Toxicol. 2016;56:23-40.
Jin L, Wang W, Fang G. Targeting protein-protein interaction by small molecules. Annu Rev Pharmacol Toxicol. 2014;54:435-56.
Adjei AA. What is the right dose? The elusive optimal biologic dose in phase I clinical trials. J Clin Oncol. 2006;24(25):4054-5.
Crews CM. Targeting the undruggable proteome: the small molecules of my dreams. Chem Biol. 2010;17(6):551-5.
Overington JP, Al‑Lazikani B, Hopkins AL. How many drug targets are there? Nat Rev Drug Discov. 2006;5(12):993-6.
Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, Zawistowski JS, et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell. 2012;149(2):307-21.
Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9(4):401-6.
Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431-5.
Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209-21.
Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464(7287):427-30.
Rauch J, Volinsky N, Romano D, Kolch W. The secret life of kinases: functions beyond catalysis. Cell Commun Signal. 2011;9(1):23.
Tan X, Thapa N, Sun Y, Anderson RA. A kinase-independent role for EGF receptor in autophagy initiation. Cell. 2015;160(1-2):145-60.
Vivanco I, Chen ZC, Tanos B, Oldrini B, Hsieh WY, Yannuzzi N, et al. A kinase- independent function of AKT promotes cancer cell survival. Elife. doi: 10.7554/eLife.03751.
Weihua Z, Tsan R, Huang WC, Wu Q, Chiu CH, Fidler IJ, et al. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell. 2008;13(5):385-93.
de Smidt PC, Le Doan T, de Falco S, van Berkel TJ. Association of antisense oligonucleotides with lipoproteins prolongs the plasma half-life and modifies the tissue distribution. Nucleic Acids Res. 1991;19(17):4695-700.
Geary RS, Watanabe TA, Truong L, Freier S, Lesnik EA, Sioufi NB, et al. Pharmacokinetic properties of 2'-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats. J Pharmacol Exp Ther. 2001;296(3):890-7.
McMahon BM, Mays D, Lipsky J, Stewart JA, Fauq A, Richelson E. Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration. Antisense Nucleic Acid Drug Dev. 2002;12(2):65-70.
Marques JT, Williams BR. Activation of the mammalian immune system by siRNAs. Nat Biotechnol. 2005;23(11):1399-405.
Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002;20:709-60.
Dahlman JE, Kauffman KJ, Langer R, Anderson DG. Nanotechnology for in vivo targeted siRNA delivery. Adv Genet. 2014;88:37-69.
Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009;8(2):129-38.
Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, Dvorak HF, et al. Analysis of nanoparticle delivery to tumours. Nat Rev Mater. doi: 10.1038/natrevmats.2016.14.
Peer D, Lieberman J. Special delivery: targeted therapy with small RNAs. Gene Ther. 2011;18(12):1127-33.
Fedorov Y, Anderson EM, Birmingham A, Reynolds A, Karpilow J, Robinson K, et al. Off-target effects by siRNA can induce toxic phenotype. RNA. 2006;12(7):1188-96.
Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, et al. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 2003;21(6):635-7.
Qiu S, Adema CM, Lane T. A computational study of off-target effects of RNA interference. Nucleic Acids Res. 2005;33(6):1834-47.
Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16(2):101-14.
Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. 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;98(15):8554-9.
Burslem GM, Crews CM. Small-molecule modulation of protein homeostasis. Chem Rev. 2017;117(17):11269-301.
Cromm PM, Crews CM. Targeted protein degradation: from chemical biology to drug discovery. Cell Chem Biol. 2017;24(9):1181-190.
Raina K, Crews CM. Targeted protein knockdown using small molecule degraders. Curr Opin Chem Biol. 2017;39:46-53.
Fisher SL, Phillips AJ. Targeted protein degradation and the enzymology of degraders. Curr Opin Chem Biol. 2018;44:47-55.
Schulman BA, Harper JW. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol. 2009;10(5):319-31.
Ye Y, Rape M. Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol. 2009;10(11):755-64.
Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem. 2009;78:399-434.
Bondeson DP, Mares A, Smith IE, Ko E, Campos S, Miah AH, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol. 2015;11(8):611-7.
Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. 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;98(15):8554-9.
Zou Y, Ma D, Wang Y. The PROTAC technology in drug development. Cell Biochem Funct. 2019;37(1):21-30.
Schneekloth AR, Pucheault M, Tae HS, Crews CM. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg Med Chem Lett. 2008;18(22):5904-8.
Burslem GM, Smith BE, Lai AC, Jaime-Figueroa S, McQuaid DC, Bondeson DP, et al. The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chem Biol. 2018;25(1):67-77.
Xue G, Wang K, Zhou D, Zhong H, Pan Z. Light-Induced Protein Degradation with Photocaged PROTACs. J Am Chem Soc. 2019;141(46):18370-4.
Naro Y, Darrah K, Deiters A. Optical Control of Small Molecule-Induced Protein Degradation. 2020;142(5):2193-7.
Li W, Elhassan RM, Fang H, Hou X. Photopharmacology-based small-molecule proteolysis targeting chimeras: optical control of protein degradation. Future Med Chem. 2020;12(22):1991-3.
Pfaff P, Samarasinghe KTG, Crews CM, Carreira EM. Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs. ACS Cent Sci. 2019;5(10):1682-90.
Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AMK, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2016;113(26):7124-9.
Velema WA, Szymanski W, Feringa BL. Photopharmacology: beyond proof of principle. J Am Chem Soc. 2014;136(6);2178-91.
Pettersson M, Crews CM. PROteolysis TArgeting Chimeras (PROTACs) - Past, present and future. Drug Discov Today Technol. doi: 10.1016/j.ddtec.2019.01.002.
Neklesa TK, Winkler JD, Crews CM. Targeted protein degradation by PROTACs. Pharmacol Ther. doi: 10.1016/j.pharmthera.2017.02.027.
Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. 2018;173(2):321-37.
