Kinase drug discovery 20 years after imatinib: progress and future directions

Nature Reviews Drug Discovery, Год журнала: 2021, Номер 20(7), С. 551 - 569

Опубликована: Май 17, 2021

Язык: Английский

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

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 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.

Язык: Английский

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Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(49), С. 20697 - 20709

Опубликована: Дек. 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.

Язык: Английский

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Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy

Journal of Hematology & Oncology, Год журнала: 2022, Номер 15(1)

Опубликована: Июль 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.

Язык: Английский

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Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors

Journal of Biological Chemistry, Год журнала: 2022, Номер 298(8), С. 102247 - 102247

Опубликована: Июль 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.

Язык: Английский

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Small molecule inhibitors targeting the cancers

MedComm, Год журнала: 2022, Номер 3(4)

Опубликована: Окт. 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.

Язык: Английский

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Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(10), С. 7668 - 7758

Опубликована: Май 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.

Язык: Английский

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Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development

ACS Omega, Год журнала: 2024, Номер unknown

Опубликована: Фев. 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.

Язык: Английский

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Novel therapeutic agents in clinical trials: emerging approaches in cancer therapy

Discover Oncology, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 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.

Язык: Английский

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Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Авг. 10, 2024

The Phosphatidylinositol-3-kinase (PI3K) family is well-known to comprise three classes of intracellular enzymes. Class I PI3Ks primarily function in signaling by responding cell surface receptor stimulation, while class II and III are more involved membrane transport. Under normal physiological conditions, the PI3K network orchestrates growth, division, migration survival. Aberrant activation pathway disrupts cellular activity metabolism, often marking onset cancer. Currently, Food Drug Administration (FDA) has approved clinical use five inhibitors. These small-molecule inhibitors, which exhibit varying selectivity for different members, used treatment breast cancer hematologic malignancies. Therefore, development novel inhibitors been a prominent research focus field oncology, aiming enhance potential therapeutic effectiveness. In this review, we summarize specific structures their functional roles progression. Additionally, critically evaluate small molecule that target PI3K, with particular on applications treatment. Moreover, aim analyze approaches types cancers marked aberrant identify molecular targets amenable intervention Ultimately, propose future directions strategies optimize outcomes modulating family.

Язык: Английский

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