Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Language: Английский

---

Annual review of PROTAC degraders as anticancer agents in 2022

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116166 - 116166

Published: Jan. 25, 2024

Language: Английский

---

Recent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(13), P. 8428 - 8440

Published: June 15, 2023

Proteolysis-targeting chimera (PROTAC) technology represents a novel and promising modality for targeted protein degradation with transformative implications the clinical management of various diseases. Despite notable advantages, possibility on-target off-tumor toxicity in healthy cells critical challenge to applications cancer treatment. Researchers are currently exploring strategies enhance activity cell-selective manner minimize undesirable side effects. In this Perspective, we highlight innovative approaches prodrug-based PROTACs (pro-PROTACs) that facilitate tumor-targeted release. The development such may further expand range potential PROTAC within drug development.

Language: Английский

---

New-generation advanced PROTACs as potential therapeutic agents in cancer therapy

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 21, 2024

Abstract Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit endogenous E3 ubiquitin ligases facilitate degradation of interest (POIs) through ubiquitin–proteasome system (UPS) in cyclic catalytic manner. Despite recent endeavors advance utilization clinical settings, majority fail progress beyond preclinical phase drug development. There are multiple factors impeding market entry PROTACs, insufficiently precise favorable POIs standing out as one most formidable obstacles. Recently, there been exploration new-generation advanced including PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, improve vivo efficacy PROTACs. These improved possess capability mitigate undesirable physicochemical characteristics inherent thereby enhancing their targetability reducing off-target side effects. The will mark pivotal turning point realm targeted protein degradation. In this comprehensive review, we meticulously summarized state-of-the-art advancements achieved by these cutting-edge elucidated underlying design principles, deliberated upon prevailing encountered, provided an insightful outlook on future prospects within field.

Language: Английский

---

Discovery of a PROTAC degrader for METTL3-METTL14 complex

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(1), P. 177 - 183.e17

Published: Jan. 1, 2024

Language: Английский

---

Targeting the undruggables—the power of protein degraders

Science Bulletin, Journal Year: 2024, Volume and Issue: 69(11), P. 1776 - 1797

Published: March 29, 2024

Undruggable targets typically refer to a class of therapeutic that are difficult target through conventional methods or have not yet been targeted, but great clinical significance. According statistics, over 80% disease-related pathogenic proteins cannot be targeted by current treatment methods. In recent years, with the advancement basic research and new technologies, development various technologies mechanisms has brought perspectives overcome challenging drug targets. Among them, protein degradation technology is breakthrough strategy for This can specifically identify directly degrade utilizing inherent pathways within cells. form includes types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting (AUTAC), (AUTOTAC), degrader-antibody conjugate (DAC). article systematically summarizes application in degraders Finally, looks forward future direction prospects technology.

Language: Английский

---

Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders

Cell chemical biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

---

Overcoming cancer therapy resistance: From drug innovation to therapeutics

Drug Resistance Updates, Journal Year: 2025, Volume and Issue: 81, P. 101229 - 101229

Published: March 8, 2025

Language: Английский

---

Antiviral PROTACs: Opportunity borne with challenge

Cell Insight, Journal Year: 2023, Volume and Issue: 2(3), P. 100092 - 100092

Published: March 27, 2023

Proteolysis targeting chimera (PROTAC) degradation of pathogenic proteins by hijacking the ubiquitin-proteasome-system has become a promising strategy in drug design. The overwhelming advantages PROTAC technology have ensured rapid and wide usage, multiple PROTACs entered clinical trials. Several antiviral been developed with bioactivities against various viruses. However, number reported is far less than that other diseases, e.g., cancers, immune disorders, neurodegenerative possibly because common deficiencies (e.g., limited available ligands poor membrane permeability) plus complex mechanism involved high tendency viral mutation during transmission replication, which may challenge successful development effective PROTACs. This review highlights important advances this rapidly growing field critical limitations encountered developing analyzing current status representative examples PROTAC-like agents. We also summarize analyze general principles strategies for design optimization intent indicating potential strategic directions future progress.

Language: Английский

---

Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(4), P. 104572 - 104572

Published: March 2, 2023

Post-translational modifications (PTMs) regulate all aspects of protein function. Therefore, upstream regulators PTMs, such as kinases, acetyltransferases, or methyltransferases, are potential therapeutic targets for human diseases, including cancer. To date, multiple inhibitors and/or agonists these PTM in clinical use, while others still development. However, control not only the PTMs disease-related target proteins but also other disease-irrelevant substrate proteins. Thus, nontargeted perturbing activities may introduce unwanted off-target toxicity issues that limit use drugs successful applications. alternative solely a specific disease-relevant provide more precise effect treating disease with relatively low side effects. this end, chemically induced proximity has recently emerged powerful research tool, and several chemical inducers (CIPs) have been used to ubiquitination, phosphorylation, acetylation, glycosylation. These CIPs high be translated into examples PROTACs MGDs now trials. Hence, need developed cover types methylation palmitoylation, thus providing full spectrum tools basic application effective cancer treatment. Eukaryotic cells rely on posttranslational activity, stability, subcellular localization, protein–protein interactions (PPIs) (1Beltrao P. Albanèse V. Kenner L.R. Swaney D.L. Burlingame A. Villén J. et al.Systematic functional prioritization modifications.Cell. 2012; 150: 413-425Abstract Full Text PDF PubMed Scopus (306) Google Scholar, 2Walsh G. Jefferis R. context proteins.Nat. Biotechnol. 2006; 24: 1241-1252Crossref (742) 3Deribe Y.L. Pawson T. Dikic I. signal integration.Nat. Struct. Mol. Biol. 2010; 17: 666-672Crossref (541) 4Peng Y. Liu H. Long mitochondrial metabolic enzymes cancer.Free Radic. Med. 2022; 179: 11-23Crossref (0) Scholar). present polar amino acids, methylation, glycosylation, whereas nonpolar acids like (Leu, L), isoleucine (Ile, I), phenylalanine (Phe, F) lack (Fig. 1). when at N terminus proteins, alanine (Ala, A), valine (Val, V), methionine (Met, M) undergo N-acetylation (5Hwang C.-S. Shemorry Varshavsky N-terminal acetylation cellular creates degradation signals.Science. 327: 973-977Crossref (467) Scholar) N-myristylation (6Thinon E. Serwa R.A. Broncel M. Brannigan J.A. Brassat U. Wright M.H. al.Global profiling co- post-translationally N-myristoylated proteomes cells.Nat. Commun. 2014; 5: 4919Crossref (161) Phosphorylation is most widely studied PTM, occurring side-chain hydroxyl group tyrosine (Tyr, Y), serine (Ser, S), threonine (Thr, T), histidine (His, H), carboxyl aspartic acid (Asp, D) glutamic (Glu, E) (7Ubersax Ferrell Jr., J.E. Mechanisms specificity phosphorylation.Nat. Rev. Cell 2007; 8: 530-541Crossref (1009) 8Attwood P.V. Besant P.G. Piggott M.J. Focus phosphoaspartate phosphoglutamate.Amino Acids. 2011; 40: 1035-1051Crossref (34) primarily affect chain some rare cases peptide can modified, seen Ala, cysteine (Cys, C), glycine (Gly, G), Met, Ser, Thr, Val (9Polevoda B. Sherman F. Nα-terminal eukaryotic proteins.J. Chem. 2000; 275: 36479-36482Abstract (285) Protein tightly regulated by network enzymatic regulators, respective writers, erasers, readers 2). As play critical role almost function, regulatory mechanism(s) downstream effect(s) being intensively many key For instance, p53 undergoes nearly PARylation, (10Kruse J.-P. Gu W. Modes regulation.Cell. 2009; 137: 609-622Abstract (1299) Consequently, effectors serve ideal particularly Several hundred small-molecule kinase, deacetylase, methyltransferase inhibitors, approved treatment, each regulator typically substrates addition target. indiscriminate inhibition effects, limiting their clinic. precisely single realistic need. In past 2 decades, proximity-induced methods, proteolysis-targeting chimera (PROTAC), having translation treatment diseases. foundation PPIs, an emerging tool manipulating PPI regulating function cells. Chemical drug-like small molecules induce remove native new (11Stanton B.Z. Chory E.J. Crabtree G.R. Chemically biology medicine.Science. 2018; 359eaao5902Crossref (169) 12Ziegler Yserentant K. Dunsing Middel Gralak A.J. Pakari al.Mandipropamid inducer vivo applications.Nat. 18: 64-69Crossref Scholar), thereby (13Winter G.E. Buckley Paulk Roberts J.M. Souza Dhe-Paganon S. al.Drug Phthalimide conjugation strategy degradation.Science. 2015; 348: 1376-1381Crossref (996) translocation (14Rivera V.M. Wang X. Wardwell Courage N.L. Volchuk Keenan al.Regulation secretion through controlled aggregation endoplasmic reticulum.Science. 287: 826-830Crossref (276) transduction (15Spencer D.M. Wandless T.J. Schreiber S.L. Controlling synthetic ligands.Science. 1993; 262: 1019-1024Crossref review, we summarize recent advances CIP technologies focus ubiquitination degradation, well novel O-linked-N-acetylglucosaminylation (O-GlcNAcylation) 3). cells, polyubiquitination ubiquitinated subsequently degraded proteasome lysosome transduce cell signals (16Hershko Ciechanover The ubiquitin system.Annu. Biochem. 1998; 67: 425-479Crossref (6931) 17Komander D. Rape code.Annu. 81: 203-229Crossref (2285) 18Vogel Nobel prizes. Gold medal from trash.Science. 2004; 306: 400-401Crossref (9) 19Kanayama Seth R.B. Sun L. Ea C.K. Hong Shaito al.TAB2 TAB3 activate NF-kappaB pathway binding polyubiquitin chains.Mol. Cell. 15: 535-548Abstract (701) This process involves sequential catalysis ubiquitin-activating enzyme E1, ubiquitin-conjugating E2, ligase E3, transfer onto lysine residues (20Dang Nie Wei Ubiquitin signaling cycle tumorigenesis.Cell Death Differ. 2021; 28: 427-438Crossref (29) reversible, deubiquitinases (DUBs) responsible removing (21Mevissen T.E. Komander deubiquitinase regulation.Annu. 2017; 86: 159-192Crossref (540) There different chains distinct biological functions due presence seven within (22Rajalingam Expanding code.Cell. 2016; 164: 1074-1074.e1Abstract example, K11 K48 mainly promote K63 usually serves docking site facilitate events (18Vogel E3 ligases dictate substrate, recognizing degron confer (23Guharoy Bhowmick Sallam Tompa Tripartite degrons diversity ubiquitin-proteasome system.Nat. 7: 10239Crossref (84) genome contains over 600 ligases, which few well-defined (24Liu Tokheim C. Lee J.D. Gan North B.J. X.S. al.Genetic fusions favor tumorigenesis loss oncogenes.Nat. 12: 6704Crossref (1) Ubiquitinated recruited 26S eliminating misfolded governing intracellular homeostasis. approaches targeted (TPD), PROTAC, molecular glue degraders (MGDs), lysosome-targeting (LYTAC), autophagy-targeting chimera, autophagosome-tethering compound, cytokine receptor-targeting (KineTAC), antibody (PROTAB) 4). methods modification interest (POI) directly recruit POI degradation. PROTAC approach hijacks endogenous system enable (25Liu Ma Xia Li Z.P. al.PROTACs: therapy.Semin. Cancer 2020; 171-179Crossref (73) molecule consists three modalities, ligand, linker bridges two ligands Various employed development, β-transducin repeat containing (26Sakamoto K.M. Kim K.B. Kumagai Mercurio Crews C.M. Deshaies R.J. Protacs: chimeric Skp1-Cullin-F box complex degradation.Proc. Natl. Acad. Sci. 2001; 98: 8554-8559Crossref (1062) von Hippel-Lindau (VHL) (27Bondeson D.P. Mares Smith I.E. Ko Campos Miah A.H. al.Catalytic knockdown PROTACs.Nat. 11: 611-617Crossref (705) MDM2 (28Schneekloth A.R. Pucheault Tae H.S. Targeted molecule: en route proteomics.Bioorg. Lett. 2008; 5904-5908Crossref (347) Cereblon (CRBN) inhibitor apoptosis 1 (29Sekine Takubo Kikuchi Nishimoto Kitagawa Abe al.Small destabilize cIAP1 activating auto-ubiquitylation.J. 283: 8961-8968Abstract (129) forms ternary corresponding ligase, facilitating (30Gadd M.S. Testa Lucas Chan K.-H. Chen Lamont D.J. al.Structural basis cooperative recognition selective degradation.Nat. 13: 514-521Crossref (556) Compared conventional acts catalytically, making it potent suppressing POI. Currently, compounds, ARV-110 ARV-447, undergoing Phase II trials prostate breast cancer, degrading androgen receptor (AR) estrogen (ER), respectively (31Gao Burris III, H.A. Vuky Dreicer Sartor A.O. Sternberg C.N. al.Phase 1/2 study ARV-110, degrader, metastatic castration-resistant (mCRPC).Am. Soc. Clin. Oncol. 17Crossref 32Hamilton Vahdat Han Ranciato Gedrich Keung C.F. al.First-in-human safety activity ARV-471, ER+/HER2-locally advanced cancer.Cancer Res. 82: PD13-PD18Crossref Although any proteasomal identification ligand remains primary challenge Interested refer comprehensive reviews further information progress (33Burslem G.M. Proteolysis-targeting chimeras therapeutics discovery.Cell. 181: 102-114Abstract (383) 34Liu Peng Inuzuka Targeting micro-environmental pathways strategy.Semin. 269-279Crossref (2) 35Békés Langley D.R. degraders: prologue.Nat. Drug Discov. 21: 181-200Crossref (299) 36Li PROTACs: past, future.Chem. 51: 5214-5236Crossref 37Dale Cheng Park K.-S. Kaniskan H.Ü. Xiong Jin Advancing therapy.Nat. Cancer. 638-654Crossref (136) class monovalent compounds bind both protein, resulting conversion neo-substrate Unlike discovery MGD serendipitous, reported phthalidomides (38Lu Middleton R.E. Naniong Ott C.J. Mitsiades C.S. al.The myeloma drug lenalidomide promotes cereblon-dependent destruction Ikaros proteins.Science. 343: 305-309Crossref (975) 39Krönke Udeshi N.D. Narla Grauman Hurst S.N. McConkey al.Lenalidomide causes IKZF1 IKZF3 cells.Science. 301-305Crossref (1104) sulfonamides (40Han Goralski Gaskill N. Capota Ting T.C. al.Anticancer splicing inducing RBM39 via recruitment DCAF15.Science. 356eaal3755Crossref (319) CR8 (41Słabicki Kozicka Z. Petzold Y.D. Manojkumar Bunker R.D. CDK degrader depletes cyclin K.Nature. 585: 293-297Crossref (144) HQ461 (42Lv Cao Zeng Cui al.Discovery promoting CDK12-DDB1 interaction trigger K degradation.Elife. 9e59994Crossref dCeMM (43Mayor-Ruiz Bauer Brand Siklos Imrichova al.Rational scalable profiling.Nat. 16: 1199-1207Crossref (121) well-studied phthalidomide thalidomide, pomalidomide, lenalidomide, specifically CRBN, adaptor CUL4 (44Ito Ando Suzuki Ogura Hotta Imamura al.Identification thalidomide teratogenicity.Science. 1345-1350Crossref (1323) neo-substrates identified, IKZF CK1α (45Krönke Fink E.C. Hollenbach P.W. MacBeth K.J. induces del (5q) MDS.Nature. 523: 183-188Crossref (536) GSPT1 (46Matyskiela M.E. Lu Ito Pagarigan C.-C. Miller al.A cereblon modulator recruits CRL4CRBN ligase.Nature. 535: 252-257Crossref ARID2 (47Yamamoto Suwa Murase Tateno Mizutome Asatsuma-Okumura al.ARID2 pomalidomide-dependent CRL4(CRBN) 1208-1217Crossref (36) PLZF (48Shimizu Yamamoto Yamaguchi Handa its fusion CRBN neosubstrates.Commun. 4: 1277Crossref SALL4 (49Donovan K.A. An Nowak R.P. Yuan J.C. Berry B.C. al.Thalidomide SALL4, transcription factor implicated duane radial ray syndrome.Elife. 7e38430Crossref (218) 50Matyskiela Couto Zheng Hui Stamp al.SALL4 mediates teratogenicity thalidomide-dependent substrate.Nat. 14: 981-987Crossref (148) p63 (51Asatsuma-Okumura De Simone Sato Shimizu al.p63 involved teratogenicity.Nat. 2019; 1077-1084Crossref (69) ZMYM2 (52Yamanaka Horiuchi Matsuoka Kido Nishino Maeno biotinylation-based identify protein-E3 glues.Nat. 183Crossref Sulfonamides, indisulam, tasisulam, chloroquinoxaline sulfonamide, CUL4-DCAF15 degrade RBM39, mRNA makes them promising could antitumor immunity synergize immune checkpoint blockades immunotherapy (53Lu S.X. Neef Thomas Sabio Rousseau Gigoux al.Pharmacologic modulation RNA enhances anti-tumor immunity.Cell. 184: 4032-4047.e1Abstract (60) Additionally, Cyclin recruiting CDK12/Cyclin DDB1-CUL4-RBX1 suggesting TPD initiated bridging stable protein. Moreover, bridge MS28 D1 conjugating VHL CDK4/6, partner (54Xiong Zhong Yim Yang K.S. Xie al.Bridged proteolysis targeting (PROTAC) enables undruggable targets.J. Am. 144: 22622-22632Crossref result, effectively degrades CDK4/6 VHL-dependent manner, than studies suggest possible transform druggable utilization bait during Besides MGD, target-specific LYTAC (55Ahn Banik S.M. C.L. Riley N.M. Cochran J.R. Bertozzi C.R. LYTACs engage asialoglycoprotein 937-946Crossref (103) 56Banik Pedram Wisnovsky Ahn Lysosome-targeting chimaeras extracellular proteins.Nature. 584: 291-297Crossref (277) PROTAB (57Marei Tsai W.K. Kee Y.S. Ruiz He Cox al.Antibody degradation.Nature. 610: 182-189Crossref (4) KineTACs (58Pance Gramespacher Byrnes Salangsang Serrano J.-A.C. Cotton A.D. al.Modular surface 41: 273-281Crossref transmembrane ATTEC (59Li Zhu Sha al.Allele-selective lowering mutant HTT HTT-LC3 compounds.Nature. 575: 203-209Crossref (196) (60Takahashi Moriyama Nakamura Miki Takahashi al.AUTACs: cargo-specific using autophagy.Mol. 76: 797-810.e10Abstract (199) lysosome-mediated utilize cation-independent mannose-6-phosphate sites lysosomal bispecific antibodies site, receptor-binding arm target-binding first example KineTAC, CXCL12 binds CXCR7, triggers endocytosis another type antibody, utilizes Zinc Ring Finger 3, plasma membrane various similarly developed, (61Bashore Prakash Johnson M.C. Conrad Kekessie I.A. Scales S.J. al.Targeted direct recruitment.Nat. 2023; 19: 55-63Crossref do require ligase. proof-of-concept macrocyclic subunit PSMD2, MC1, conjugated bromodomain (BRD)-4 BETi, facilitates BRD4 without prior stabilization increasing avenue extensively tested diseases (62Manasanch E.E. Orlowski R.Z. Proteasome 417-433Crossref (538) 63Liu Zhang SCF therapies.Adv. Exp. 1217: 123-146Crossref (26) major limitation broad range given stabilize sparing purposes. Abnormal certain contributes pathologies, cystic fibrosis, caused (F508) deletion fibrosis conductance

Language: Английский

---