Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103799 - 103799
Published: Oct. 13, 2023
Language: Английский
Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(7), P. 551 - 569
Published: May 17, 2021
Language: Английский
Citations
794
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
Citations
184
Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(49), P. 20697 - 20709
Published: Dec. 3, 2021
The main protease (Mpro) is a validated antiviral drug target of SARS-CoV-2. A number Mpro inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet be addressed the selectivity over host proteases such as cathepsin L. In this we describe rational design covalent SARS-CoV-2 with novel cysteine reactive warheads including dichloroacetamide, dibromoacetamide, tribromoacetamide, 2-bromo-2,2-dichloroacetamide, 2-chloro-2,2-dibromoacetamide. promising lead candidates Jun9-62-2R (dichloroacetamide) Jun9-88-6R (tribromoacetamide) had not only potent enzymatic inhibition activity but also significantly improved specificity caplain cathepsins. Compared GC-376, these new compounds did inhibit calpain I, B, K, L, caspase-3. To best our knowledge, they are among most selective reported thus far. cocrystal structures Jun9-57-3R reaffirmed hypothesis, showing that both form adduct catalytic C145. Overall, represent valuable chemical probes for validation further development antivirals.
Language: Английский
Citations
124
Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)
Published: July 7, 2022
Abstract Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor protein tyrosine kinases that play an important role in the regulation tumor-induced angiogenesis. Currently, VEGFR inhibitors have been widely used treatment various tumors. However, current limited to certain extent due clinical efficacy and potential toxicity, which hinder their application. Thus, development new strategies improve outcomes minimize toxic effects is required. Given synergistic effect other therapies tumor progression, dual-target becoming attractive approach favorable pharmacodynamics, low anti-resistant effects. This perspective provides overview from multiple aspects, including rational target combinations, drug discovery strategies, structure–activity relationships future directions.
Language: Английский
Citations
107
Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 298(8), P. 102247 - 102247
Published: July 10, 2022
Protein kinases are key components in cellular signaling pathways as they carry out the phosphorylation of proteins, primarily on Ser, Thr, and Tyr residues. The catalytic activity protein is regulated, can be thought molecular switches that controlled through protein-protein interactions post-translational modifications. exhibit diverse structural mechanisms regulation have been fascinating subjects for biologists from first crystal structure a kinase over 30 years ago, to recent insights into assemblies enabled by breakthroughs cryo-EM. high-priority targets drug discovery oncology other disease settings, inhibitors transformed outcomes specific groups patients. Most ATP competitive, deriving potency occupying deep hydrophobic pocket at heart domain. Selectivity depends exploiting differences between amino acids line site exploring surrounding pockets present inactive states kinase. More recently, allosteric outside being targeted achieve high selectivity overcome resistance current therapeutics. Here, we review regulatory features family, describe different types inhibitors, highlight examples where understanding has gone hand with development inhibitors.
Language: Английский
Citations
104
MedComm, Journal Year: 2022, Volume and Issue: 3(4)
Published: Oct. 13, 2022
Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary therapies for cancer. Due to their advantages a wide range targets, convenient medication, ability penetrate into central nervous system, many efforts have been devoted developing more small inhibitors. To date, 88 approved by United States Food Drug Administration treat cancers. Despite remarkable progress, cancer treatment still face obstacles, such as low response rate, short duration response, toxicity, biomarkers, resistance. better promote development targeting cancers, we comprehensively reviewed involved all agents pivotal drug candidates clinical trials arranged signaling pathways classification We discussed lessons learned from these agents, proper strategies overcome resistance arising different mechanisms, combination concerned Through our review, hoped provide insights perspectives research treatment.
Language: Английский
Citations
95
Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7668 - 7758
Published: May 7, 2024
Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.
Language: Английский
Citations
57
Discover Oncology, Journal Year: 2024, Volume and Issue: 15(1)
Published: Aug. 11, 2024
Novel therapeutic agents in clinical trials offer a paradigm shift the approach to battling this prevalent and destructive disease, area of cancer therapy is on precipice trans formative revolution. Despite importance tried-and-true treatments like surgery, radiation, chemotherapy, disease continues evolve adapt, making new, more potent methods necessary. The field currently witnessing emergence wide range innovative approaches. Immunotherapy, including checkpoint inhibitors, CAR-T cell treatment, vaccines, utilizes host's immune system selectively target eradicate malignant cells while minimizing harm normal tissue. development targeted medicines kinase inhibitors monoclonal antibodies has allowed for less harmful approaches treating cancer. With help genomics molecular profiling, "precision medicine" customizes therapies each patient's unique genetic makeup maximize efficacy unwanted side effects. Epigenetic therapies, metabolic interventions, radio-pharmaceuticals, an increasing emphasis combination with synergistic effects further broaden landscape. Multiple-stage are essential determining safety these novel drugs, allowing patients gain access also furthering scientific understanding. future rife promise, as integration artificial intelligence big data potential revolutionize early detection prevention. Collaboration among researchers, healthcare providers, active involvement remain bedrock ongoing battle against In conclusion, dynamic evolving landscape provides hope improved treatment outcomes, emphasizing patient-centered, data-driven, ethically grounded we collectively strive towards cancer-free world.
Language: Английский
Citations
28
ACS Omega, Journal Year: 2024, Volume and Issue: unknown
Published: Feb. 8, 2024
Understanding enzyme mechanisms is essential for unraveling the complex molecular machinery of life. In this review, we survey field computational enzymology, highlighting key principles governing and discussing ongoing challenges promising advances. Over years, computer simulations have become indispensable in study mechanisms, with integration experimental exploration now established as a holistic approach to gain deep insights into enzymatic catalysis. Numerous studies demonstrated power characterizing reaction pathways, transition states, substrate selectivity, product distribution, dynamic conformational changes various enzymes. Nevertheless, significant remain investigating multistep reactions, large-scale changes, allosteric regulation. Beyond mechanistic studies, modeling has emerged an tool computer-aided design rational discovery covalent drugs targeted therapies. Overall, design/engineering drug development can greatly benefit from our understanding detailed enzymes, such protein dynamics, entropy contributions, allostery, revealed by studies. Such convergence different research approaches expected continue, creating synergies research. This outlining ever-expanding research, aims provide guidance future directions facilitate new developments important evolving field.
Language: Английский
Citations
27
Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)
Published: Dec. 5, 2024
Abstract Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered be undruggable targets have become increasingly feasible due the progress that has been made over last two decades rapid technological advances. This work explores influence of innovations on PPI research development. Additionally, diverse strategies for discovering, modulating, characterizing PPIs their corresponding modulators examined with aim presenting a streamlined pipeline advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in modulator discovery development, we illustrate efficacy various identifying, optimizing, overcoming challenges associated design. The valuable lessons insights gained from identification, optimization, approval discussed demonstrating transitioned beyond early-stage now represent prime opportunity significant potential. examples encompass those developed cancer, inflammation immunomodulation, well antiviral applications. perspective aims establish foundation effective targeting modulation using pave way future
Language: Английский
Citations
22