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

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

Published: Aug. 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.

Language: Английский

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10 Years Into the Resurgence of Covalent Drugs

Future Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 13(2), P. 193 - 210

Published: Dec. 4, 2020

In the first decade of targeted covalent inhibition, scientists have successfully reversed previous trend that had impeded use inhibition in drug development. Successes clinic, mainly field kinase inhibitors, are existing proof safe inhibitors can be designed and employed to develop effective treatments. The case KRASG12C entering clinical trials 2019 has been among hottest topics discussed discovery, raising expectations for future field. this perspective, an overview milestones hit with as well promise needs current research, presented. While recent results confirmed potential was foreseen, many questions remain unexplored branch precision medicine.

Language: Английский

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Discovery of Cysteine-targeting Covalent Protein Kinase Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 65(1), P. 58 - 83

Published: Dec. 28, 2021

Small molecule covalent kinase inhibitors (CKIs) have entered a new era in drug discovery, which the advantage for sustained target inhibition and high selectivity. An increased understanding of binding kinetics CKIs discovery additional irreversible reversible-covalent cysteine-targeted warheads has inspired development this area. Herein, we summarize major medicinal chemistry strategies employed these representative CKIs, are categorized by location cysteine within seven main regions kinase: front region, glycine rich loop (P-loop), hinge DFG activation (A-loop), catalytic (C-loop), remote loop. The emphasis is placed on design optimization that generated addition warhead to reversible lead/inhibitor scaffold. In addition, address challenges facing area discovery.

Language: Английский

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Covalent inhibition of NSD1 histone methyltransferase

Nature Chemical Biology, Journal Year: 2020, Volume and Issue: 16(12), P. 1403 - 1410

Published: Aug. 31, 2020

Language: Английский

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Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(13), P. 4979 - 4992

Published: March 25, 2021

Targeted covalent inhibitors are an important class of drugs and chemical probes. However, relatively few electrophiles meet the criteria for successful inhibitor design. Here we describe α-substituted methacrylamides as a new suitable targeted inhibitors. While typically α-substitutions inactivate acrylamides, show that hetero have higher thiol reactivity undergo conjugated addition–elimination reaction ultimately releasing substituent. Their toward thiols is tunable correlates with pKa/pKb leaving group. In context BTK ibrutinib, these showed lower intrinsic than unsubstituted ibrutinib acrylamide. This translated to comparable potency in protein labeling, vitro kinase assays, functional cellular improved selectivity. The conjugate upon binding their target cysteine allows functionalizing turn-on To demonstrate this, prepared ligand directed release (CoLDR) fluorescent probes BTK, EGFR, K-RasG12C. We further CoLDR chemiluminescent probe enabled high-throughput screen Altogether represent versatile addition toolbox

Language: Английский

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A Comprehensive Guide for Assessing Covalent Inhibition in Enzymatic Assays Illustrated with Kinetic Simulations

Current Protocols, Journal Year: 2022, Volume and Issue: 2(6)

Published: June 1, 2022

Covalent inhibition has become more accepted in the past two decades, as illustrated by clinical approval of several irreversible inhibitors designed to covalently modify their target. Elucidation structure-activity relationship and potency such requires a detailed kinetic evaluation. Here, we elucidate between experimental read-out underlying inhibitor binding kinetics. Interactive simulation scripts are employed highlight effects vitro enzyme activity assay conditions mode, thereby showcasing which assumptions corrections crucial. Four stepwise protocols assess biochemical (ir)reversible covalent targeting nucleophilic active site residue included, with accompanying data analysis tailored mode. Together, this will serve guide make an educated decision regarding most suitable method potency. © 2022 The Authors. Current Protocols published Wiley Periodicals LLC. Basic Protocol I: Progress curve substrate association competition Data Analysis 1A: Two-step 1B: One-step 1C: reversible 1D: depletion II: Incubation time-dependent IC50 (t) 2: III: Preincubation without dilution 3: 3Ai: Alternative 3Aii: 3Bi: 3Bii: 3C: IV: dilution/competition 4: 4Ai: 4Aii: 4Bi: 4Bii: inhibition.

Language: Английский

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Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

Frontiers in Chemistry, Journal Year: 2022, Volume and Issue: 10

Published: April 14, 2022

Targeted therapy is a groundbreaking innovation for cancer treatment. Among the receptor tyrosine kinases, fibroblast growth factor receptors (FGFRs) garnered substantial attention as promising therapeutic targets due to their fundamental biological functions and frequently observed abnormality in tumors. In past 2 decades, several generations of FGFR kinase inhibitors have been developed. This review starts by introducing basis FGF/FGFR signaling. It then gives detailed description different types small-molecule according modes action, followed systematic overview small-molecule-based therapies modalities. ends with our perspectives development novel inhibitors.

Language: Английский

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Cell‐Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR‐ABL Kinase

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(26)

Published: April 19, 2022

Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a develop cell-active inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. validated strategy successfully (irreversible reversible) against BCR-ABL kinase. Our lead compounds showed high levels selectivity biochemical assays, exhibited nanomolar potency endogenous ABL kinase cellular were active most drug-resistant mutations. Among them, salicylaldehyde-containing A5 first-ever reversible inhibitor that possessed time-dependent inhibition with prolonged residence time few off-targets K562 cells. Bioinformatics further suggested generality our human kinome.

Language: Английский

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Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(14), P. 6326 - 6342

Published: March 30, 2022

Covalent protein kinase inhibitors exploit currently noncatalytic cysteines in the adenosine 5′-triphosphate (ATP)-binding site via electrophiles directly appended to a reversible-inhibitor scaffold. Here, we delineate path target solvent-exposed at distance >10 Å from an ATP-site-directed core module and produce potent covalent phosphoinositide 3-kinase α (PI3Kα) inhibitors. First, reactive warheads are used reach out Cys862 on PI3Kα, second, enones replaced with druglike while linkers optimized. The systematic investigation of intrinsic warhead reactivity (kchem), rate bond formation proximity (kinact reaction space volume Vr), integration structure data, kinetic structural modeling, led guided identification high-quality, chemical probes. A novel stochastic approach provided direct access calculation overall rates as function kchem, kinact, Ki, Vr, which was validated compounds varied linker lengths. X-ray crystallography, mass spectrometry (MS), NanoBRET assays confirmed acrylamide Cys862. In rat liver microsomes, 19 22 outperformed rapidly metabolized CNX-1351, only known PI3Kα irreversible inhibitor. Washout experiments cancer cell lines mutated, constitutively activated showed long-lasting inhibition PI3Kα. SKOV3 cells, revealed PI3Kβ-dependent signaling, sensitive TGX221. Compounds thus qualify specific probes explore PI3Kα-selective signaling branches. proposed is generally suited develop tools targeting distal, unexplored Cys residues biologically active enzymes.

Language: Английский

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Nitriles: an attractive approach to the development of covalent inhibitors

RSC Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 14(2), P. 201 - 217

Published: Nov. 7, 2022

Nitriles have broad applications in medicinal chemistry, with more than 60 small molecule drugs on the market containing cyano functional group. In addition to well-known noncovalent interactions that nitriles can perform macromolecular targets, they are also known improve drug candidates' pharmacokinetic profiles. Moreover, group be used as an electrophilic warhead covalently bind inhibitor a target of interest, forming covalent adduct, strategy present benefits over inhibitors. This approach has gained much notoriety recent years, mainly diabetes and COVID-19-approved drugs. Nevertheless, application ligands is not restricted it being reactive center, employed convert irreversible inhibitors into reversible ones, promising for kinase inhibition protein degradation. this review, we introduce discuss roles inhibitors, how tune its reactivity possibility achieving selectivity only by replacing warhead. Finally, provide overview nitrile-based compounds approved recently described literature.

Language: Английский

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