Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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Proximity-Based Modalities for Biology and Medicine

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(7), P. 1269 - 1284

Published: July 14, 2023

Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of processes high selectivity has the potential to substantially expand target space. A plethora proximity-based modalities proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines mechanisms molecules based on induced proximity, including protein degraders, blockers, stabilizers, inducers post-translational modifications, agents cell therapy, discusses challenges that field must address mature unlock translation in biology medicine.

Language: Английский

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Expanding the horizons of targeted protein degradation: A non-small molecule perspective

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(6), P. 2402 - 2427

Published: Jan. 21, 2024

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel

Language: Английский

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Updates in Alzheimer's disease: from basic research to diagnosis and therapies

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Sept. 4, 2024

Language: Английский

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Targeting Tau Protein with Proximity Inducing Modulators: A New Frontier to Combat Tauopathies

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(3), P. 654 - 672

Published: Feb. 10, 2025

Dysregulation of correct protein tau homeostasis represents the seed for development several devastating central nervous system disorders, known as tauopathies, that affect millions people worldwide. Despite massive public and private support to research funding, these diseases still represent unmet medical needs. In fact, tau-targeting tools developed date have failed translate into clinic. Recently, taking advantage modes nature uses mediate flow information in cells, researchers a new class molecules, called proximity-inducing modulators, which exploit spatial proximity modulate function(s) redirect cellular processes. this perspective, after brief discussion about classic approaches, we will discuss different classes modulators so far highlight applications protein's function tau-induced toxicity.

Language: Английский

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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

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Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review

Molecules, Journal Year: 2024, Volume and Issue: 29(12), P. 2812 - 2812

Published: June 13, 2024

Tau protein is a microtubule-associated that widely distributed in the central nervous system and maintains regulates neuronal morphology function. aggregates abnormally forms neurofibrillary tangles neurodegenerative diseases, disrupting structure function of neurons leading to death, which triggers initiation progression neurological disorders. The aggregation tau diseases associated with post-translational modifications, may affect hydrophilicity, spatial conformation, stability protein, promoting formation tangles. Therefore, studying role mechanism aberrant important for understanding finding therapeutic approaches. This review describes possible mechanisms by promotes modifications influencing factors, current status drug discovery development related contribute new approaches alleviate or treat diseases.

Language: Английский

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Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(14), P. 9779 - 9789

Published: April 1, 2024

Protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis O-GlcNAcylation has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- site-specific O-GlcNAc modification, rendering precise study challenging. To address this, we have developed heterobifunctional small molecules, named TArgeting Chimeras (OGTACs), which enable protein-specific living cells. OGTACs promote proteins such as BRD4, CK2α, EZH2 cellulo by recruiting FKBP12F36V-fused transferase (OGT), with temporal, magnitude, reversible control. Overall, represent promising approach inducing O-GlcNAcylation, thus enabling functional dissection offering new directions O-GlcNAc-targeting therapeutic development.

Language: Английский

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EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling

Science Advances, Journal Year: 2024, Volume and Issue: 10(13)

Published: March 27, 2024

We recently developed a heterobifunctional approach [phosphorylation targeting chimeras (PhosTACs)] to achieve the targeted protein dephosphorylation (TPDephos). Here, we envisioned combining inhibitory effects of receptor tyrosine kinase inhibitors (RTKIs) and active by phosphatases dual inhibition kinases. report an example phosphatase–based TPDephos effective epidermal growth factor (EGFR) dephosphorylation. also used phosphoproteomic approaches study signaling transductions affected PhosTAC-related molecules at proteome-wide level. This work demonstrated differential pathways inhibited PhosTAC compared with TKI, gefitinib. Moreover, covalent selective for mutated EGFR was showed its potential dysregulated EGFR. Last, PhosTACs, consistent profiles, induced apoptosis cancer cell viability during prolonged treatment. PhosTACs showcased their modulating RTKs activity, expanding scope bifunctional molecule utility.

Language: Английский

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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

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