Overcoming Secondary Mutations of Type II Kinase Inhibitors

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(12), С. 9776 - 9788

Опубликована: Июнь 5, 2024

Type II kinase inhibitors bind in the "DFG-out" conformation and are generally considered to be more potent selective than type I inhibitors, which target a DFG-in conformation. Nine currently clinically approved, with undergoing clinical development. Resistance-conferring secondary mutations emerged first series of most commonly at residues within activation loop "gatekeeper" position. Recently, new have been developed overcome such mutations; however, activating other pathways (and/or targets) subsequently on occasion. Here, we systematically summarize that confer resistance structural basis for resistance, newer designed as well challenges opportunities development domain mutations.

Язык: Английский

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Breath and Beyond: Advances in Nanomedicine for Oral and Intranasal Aerosol Drug Delivery

Pharmaceuticals, Год журнала: 2024, Номер 17(12), С. 1742 - 1742

Опубликована: Дек. 23, 2024

Designing and standardizing drug formulations are crucial for ensuring the safety efficacy of medications. Nanomedicine utilizes nano delivery systems advanced nanodevices to address numerous critical medical challenges. Currently, oral intranasal aerosol (OIADD) is primary method treating respiratory diseases worldwide. With advancements in disease understanding development aerosolized systems, application OIADD has exceeded its traditional boundaries, demonstrating significant potential treatment non-respiratory conditions as well. This study provides a comprehensive overview applications treatment. It examines key challenges limiting nanomedicines formulation processes, devices explores latest these areas. review aims offer valuable insights researchers involved platforms.

Язык: Английский

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Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action

Biomedicines, Год журнала: 2023, Номер 11(10), С. 2599 - 2599

Опубликована: Сен. 22, 2023

Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention the site of action is difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain binding days despite rapid plasma clearance, minimal non-diseased tissues, metabolism. They have shown significant therapeutic value cancer neurodegenerative diseases by disassembling epichaperomes, assemblies tightly bound chaperones other factors that serve scaffolding platforms pathologically rewire protein–protein interactions. To investigate impact epichaperomes vivo, conducted pharmacokinetic occupancy measurements monitored biochemically mouse model. Our findings provide evidence intricate mechanism through modulates vivo. Initially, becomes trapped when bound, results disassembly, no change expression level constituents. We propose initial trapping stage main contributing factor extended on-target observed agent clinical settings. Zelavespib’s tumors seems be dictated disassembly kinetics rather than frank drug–target unbinding kinetics. off-rate from is, therefore, much slower anticipated recorded tumor profile or determined vitro using diluted systems. This research sheds light underlying processes make agents effective treatment certain diseases.

Язык: Английский

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Allosteric crosstalk in modular proteins: Function fine-tuning and drug design

Computational and Structural Biotechnology Journal, Год журнала: 2023, Номер 21, С. 5003 - 5015

Опубликована: Янв. 1, 2023

Modular proteins are regulatory that carry out more than one function. These upregulate or downregulate a biochemical cascade to establish homeostasis in cells. To switch the function alter efficiency (based on cellular needs), these require different facilitators bind site from catalytic (active/orthosteric) site, aka 'allosteric site', and fine-tune their (or effectors) allosteric modulators. In this Review, we have discussed allostery, characterized them based mechanisms, how allostery plays an important role activity modulation fine-tuning of proteins. Recently there is emergence discovery drugs. We also emphasized role, significance, future therapeutic applications.

Язык: Английский

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A Comparative Study of Chemical Profiling and Bioactivities between Thai and Foreign Hemp Seed Species (Cannabis sativa L.) Plus an In-Silico Investigation

Foods, Год журнала: 2023, Номер 13(1), С. 55 - 55

Опубликована: Дек. 22, 2023

Hemp (

Язык: Английский

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In vitro cleavage of tumor necrosis factor α (TNFα) by Signal-Peptide-Peptidase-like 2b (SPPL2b) resembles mechanistic principles observed in the cellular context

Chemico-Biological Interactions, Год журнала: 2024, Номер 395, С. 111006 - 111006

Опубликована: Апрель 16, 2024

Members of the Signal Peptide-Peptidase (SPP) and Peptide-Peptidase-like (SPPL) family are intramembrane aspartyl-proteases like their well-studied homologs, presenilins, which comprise catalytically active subunit within γ-secretase complex. The lack in vitro cleavage assays for SPPL proteases limited biochemical characterization as well substrate identification validation. So far, have been analyzed exclusively intact cells or membranes, restricting mechanistic analysis to co-expression enzyme variants colocalizing same subcellular compartments. We describe details developing an assay SPPL2b its model TNFα influence phospholipids, detergent supplements, cholesterol on activity. activity resembles principles that observed a cellular context, such sites consecutive turnover transmembrane domain. novel is functional with separately isolated protease amenable high throughput plate-based readout overcoming previous limitations providing basis studying kinetics, catalytic activity, recognition, characteristics small molecule inhibitors. As proof concept, we present first SPPL2a specific inhibitor SPL-707.

Язык: Английский

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Rapid Determination of Kinetic Constants for Slow-Binding Inhibitors and Inactivators of Human Histone Deacetylase 8

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 5593 - 5593

Опубликована: Май 21, 2024

The kinetics and mechanism of drug binding to its target are critical pharmacological efficacy. A high throughput (HTS) screen often results in hundreds hits, which usually only simple IC50 values determined during reconfirmation. However, kinetic parameters such as residence time for reversible inhibitors the kinact/KI ratio, is measure evaluating covalent inactivators, early predictive measures assess chances success hits clinic. Using promising cancer human histone deacetylase 8 an example, we present a robust method that calculates concentration-dependent apparent rate constants inhibition or inactivation HDAC8 from dose–response curves recorded after different pre-incubation times. With these data, hit compounds can be classified according their action, relevant calculated highly parallel fashion. with known modes action were correctly assigned mechanism, mechanisms some internal screening campaign newly determined. oxonitriles SVE04 SVE27 fast moderate time-constant 4.2 2.6 µM, respectively. compound TJ-19-24 SAH03 behave like slow two-step inactivators inhibitors, very low reverse isomerization rate.

Язык: Английский

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Calculating Protein-Ligand Residence Times Through State Predictive Information Bottleneck based Enhanced Sampling

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 20, 2024

Abstract Understanding drug residence times in target proteins is key to improving efficacy and understanding recognition biochemistry. While time just as important binding affinity, atomiclevel of through molecular dynamics (MD) simulations has been difficult primarily due the extremely long timescales. Recent advances rare event sampling have allowed us reach these timescales, yet predicting protein-ligand remains a significant challenge. Here we present semi-automated protocol calculate ligand across 12 orders magnitudes In our proposed framework, integrate deep learning-based method, state predictive information bottleneck (SPIB), learn an approximate reaction coordinate (RC) use it guide enhanced method metadynamics. We demonstrate performance algorithm by applying six different complexes with available benchmark times, including dissociation widely studied anti-cancer Imatinib (Gleevec) from both wild-type Abl kinase drug-resistant mutants. show how can recover quantitatively accurate potentially opening avenues for deeper insights into development possibilities mechanisms. TOC Graphic

Язык: Английский

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Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 19, 2024

Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and promising therapeutic target in inflammatory diseases. Here, we synthesize competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest the interaction of KSI-6666 with methionine residue Met124 ligand-binding pocket may inhibit dissociation from S1PR1. Consistently, vitro functional mutational analyses reveal causes pseudoirreversible inhibition S1PR1, dependent on protein substituents distal benzene ring KSI-6666. Moreover, vivo study suggests this responsible persistent activity

Язык: Английский

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Advances in binding kinetics and mechanistic PK/PD modelling

British Journal of Pharmacology, Год журнала: 2024, Номер 181(21), С. 4089 - 4090

Опубликована: Сен. 15, 2024

Язык: Английский

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