Fotokontrolisani PROTAC molekuli – struktura i mehanizam dejstva
Sažetak
Tradicionalne strategije razvoja lekova su obično osvrnute na okupiranje vezujućih mesta koja direktno utiču na funkcije proteina. Stoga se proteini koji nemaju takva vezujuća mesta generalno smatraju farmakološki nedodirljivim. Modulatori aktivnosti proteina, naročito inhibitori, koriste se u režimima doziranja koji često dovode do preterane sistemske izloženosti leku, a sve u cilju održavanja dovoljne inhibicije proteina in vivo. Posledično, postoji rizik od neželjenog vezivanja leka van svog primarnog mesta dejstva i neželjenih efekata. Nedavno je predstavljena tehnologija dirigovane proteolize (PROteolysis TArgeting Chimera, PROTAC) kao novi farmakološki modalitet koji koristi PROTAC molekule za indukovanu degradaciju proteina. PROTAC molekuli su heterobifunkcionalne strukture sačinjene od liganda koji se vezuje za protein od interesa (POI), liganda za regrutovanje E3 ubikvitin ligaze (enzima uključenog u ubikvitinaciju POI) i linkera koji ih povezuje. Nakon formiranja ternarnog kompleksa POI-PROTAC-E3 ubikvitin ligaza, POI podleže ubikvitinaciji (enzimskoj post-translacionoj modifikaciji u kojoj se ubikvitin vezuje za POI) i degradaciji. Integrisanjem principa fotofarmakologije i PROTAC tehnologije, nedavno su nastali su fotokontrolisani PROTAC molekuli za prostorno-vremensku kontrolu indukovane degradacije proteina. Zahvaljujući lokalnoj fotoaktivaciji, glavna prednost fotokontrolisanih nad konvencionalnim PROTAC molekulima je moguća prevencija toksičnosti koja nastaje usled dejstva van primarnog biološkog targeta.
Reference
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.
- Autori zadržavaju autorska prava i pružaju časopisu pravo prvog objavljivanja rada i licenciraju ga "Creative Commons Attribution licencom" koja omogućava drugima da dele rad, uz uslov navođenja autorstva i izvornog objavljivanja u ovom časopisu.
- Autori mogu izraditi zasebne, ugovorne aranžmane za neekskluzivnu distribuciju članka objavljenog u časopisu (npr. postavljanje u institucionalni repozitorijum ili objavljivanje u knjizi), uz navođenje da je članak izvorno objavljen u ovom časopisu.
- Autorima je dozvoljeno i podstiču se da postave objavljeni članak onlajn (npr. u institucionalni repozitorijum ili na svoju internet stranicu) pre ili tokom postupka prijave rukopisa, s obzirom da takav postupak može voditi produktivnoj razmeni ideja i ranijoj i većoj citiranosti objavljenog članka (Vidi Efekti otvorenog pristupa).