Integration of Consensus‐Based Pharmacophore Mapping and Molecular Docking in Sequential Virtual Screening: Toward the Discovery of Novel PI3Kγ Inhibitors DOI

X Yu,

Shiru Yuan,

Lei Jia

и другие.

ChemistrySelect, Год журнала: 2024, Номер 9(41)

Опубликована: Окт. 28, 2024

Abstract Numerous research studies have demonstrated the significant correlation of phosphatidylinositol‐3 kinase gamma (PI3Kγ) with onset and progression various human diseases, highlighting PI3Kγ as a promising therapeutic target. However, demonstrates considerable similarity other isoforms in PI3K family, presenting challenges creation inhibitors. This study presents an ensemble‐based virtual screening approach to discover novel inhibitors targeting PI3Kγ. Eganelisib (IPI‐549) is sole selective inhibitor that has progressed clinical trials, making it model for advancement Initially, common feature pharmacophore receptor–ligand models were independently developed using IPI‐549 its potent derivatives, conjunction crystal complex PI3Kγ/IPI‐549. Both qualitative proved highly effective at distinguishing between active inactive compounds. Then, four widely utilized docking programs chosen assessment, where Glide_SP mode superior predictive accuracy sampling ligand conformations during binding, effectively noninhibitors. Finally, protocol was conducted screen ChEMBL database, utilizing search, consensus‐based mapping, sequential molecular docking. process resulted identification multiple molecules exhibiting notable promise

Язык: Английский

An Analysis of PIK3CA Hotspot Mutations and Response to Neoadjuvant Therapy in Patients with Breast Cancer from Four Prospective Clinical Trials DOI
Paul Jank, Thomas Karn, Marion van Mackelenbergh

и другие.

Clinical Cancer Research, Год журнала: 2024, Номер 30(17), С. 3868 - 3880

Опубликована: Июнь 5, 2024

The PI3K signaling pathway is frequently dysregulated in breast cancer, and mutations PIK3CA are relevant for therapy resistance HER2-positive (HER2pos) cancer. Mutations exons 9 or 20 may have different impacts on response to neoadjuvant chemotherapy-based treatment regimens.

Язык: Английский

Процитировано

3
Isoflavone Derivatives as Potential Anticancer Agents: Synthesis and Bioactivity Studies DOI Creative Commons
Mamoalosi A. Selepe

ChemMedChem, Год журнала: 2024, Номер unknown

Опубликована: Авг. 2, 2024

Isoflavones are phenolic natural compounds with a C

Язык: Английский

Процитировано

3
Important Roles of PI3K/AKT Signaling Pathway and Relevant Inhibitors in Prostate Cancer Progression DOI Creative Commons

Rui Wang,

Zhen Qu,

Ying Lv

и другие.

Cancer Medicine, Год журнала: 2024, Номер 13(21)

Опубликована: Ноя. 1, 2024

Prostate cancer (PCa) is an extremely common malignant tumor of the male genitourinary system, originating from prostate gland epithelium. Male patients are prone to relapse after treatment, which seriously threatens their health. Phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB, also known as Akt) plays important role in growth, invasion, and metastasis PCa. This review aimed present overview mechanism action PI3K/AKT signaling pathway PCa discuss application prospects inhibitors this treating PCa, providing a theoretical basis reference for its clinical treatment targets.

Язык: Английский

Процитировано

3
Evaluating the Anti-inflammatory Potential of JN-KI3: The Therapeutic Role of PI3Kγ-Selective Inhibitors in Asthma Treatment DOI

Lei Jia,

Mengyun Ma,

Wendian Xiong

и другие.

Inflammation, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

Язык: Английский

Процитировано

0
Targeting PI3K in Cancer Treatment: A Comprehensive Review with Insights from Clinical Outcomes DOI
Munier Hossain, Md. Arafat Hossain

European Journal of Pharmacology, Год журнала: 2025, Номер unknown, С. 177432 - 177432

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

0
Lysine-Targeted Covalent Strategy Leading to the Discovery of Novel Potent PROTAC-Based PI3Kδ Degraders DOI
Bo Yuan, Jiaxin Liu, Yujie Wu

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Май 31, 2025

Proteolysis-targeting chimera (PROTAC) technology was employed to achieve the degradation of PI3Kδ in this study, and a series PROTAC-based degraders were first developed. Lysine-targeted covalent strategy led discovery novel potent degraders. After screening structure-activity relationship B14 optimal exhibited strong antiproliferation selective inhibition, with high value (DC50 = 3.98 nM). induced cell cycle arrest premitotic phase prompted apoptosis. displayed effective suppression tumor growth xenograft model significantly promoted vivo. Most importantly, bound Lys779 selectively degrade by covalent-bonding. Mechanistic studies indicated that ubiquitin-proteasome pathway involved process. This study provided an approach for developing degraders, lysine-targeted laid foundation further design PI3Kδ-targeting PROTACs.

Язык: Английский

Процитировано

0
Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition DOI Creative Commons
Murat Kücükdisli,

Hassen Bel-Abed,

Davide Cirillo

и другие.

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(20), С. 14278 - 14302

Опубликована: Окт. 11, 2023

Class II phosphoinositide-3-kinases (PI3Ks) play central roles in cell signaling, division, migration, and survival. Despite evidence that all PI3K class isoforms serve unique cellular functions, the lack of isoform-selective inhibitors severely hampers systematic investigation their potential relevance as pharmacological targets. Here, we report structural evaluation molecular determinants for selective PI3K-C2α inhibition by a structure–activity relationship study based on pteridinone scaffold, leading to discovery called PITCOINs. Cocrystal structures docking experiments supported rationalization essential inhibitor activity high selectivity. Profiling PITCOINs panel more than 118 diverse kinases showed no off-target kinase inhibition. Notably, addressing selectivity pocket, PITCOIN4 nanomolar >100-fold general panel. Our paves way development novel therapies diseases related function.

Язык: Английский

Процитировано

3
Evaluating the anti-inflammatory potential of JN-KI3: the therapeutic role of PI3Kγ- selective inhibitors in asthma treatment DOI Creative Commons
Lei Jia,

Mengyun Ma,

Wendian Xiong

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Янв. 18, 2024

Abstract Introduction Asthma is a chronic airway inflammatory disease of the airways characterized by involvement numerous cells and factors. Therefore, targeting inflammation one crucial strategies for developing novel drugs in treatment asthma. Phosphoinositide 3-kinase gamma (PI3Kγ) has been demonstrated to have significant impact on immune responses, thus emerging as promising therapeutic target disease, including Objective method There are few studies reporting effects PI3Kγ-selective inhibitors asthma disease. In this study, we investigated anti-inflammatory inhibitor JN-KI3 treating utilizing both vivo vitro approaches, thereby proving that could be valuable Results RAW264.7 macrophages, effectively suppressed C5a-induced Akt phosphorylation concentration-dependent manner, with no discernible toxicity observed cells. Furthermore, can inhibit PI3K/Akt signaling pathway lipopolysaccharide-induced cells, leading suppression transcription expression classical cytokines manner. Finally, an ovalbumin-induced murine model was constructed evaluate initial effect Oral administration inhibited infiltration T-helper type 2 bronchoalveolar lavage fluid, which associated PI3K pathway. Lung tissue immunohistochemical accumulation around bronchus blood vessels, well secretion mucus excessive deposition collagen airway. addition, it reduced white into lungs. Conclusion shows promise candidate Our study also suggests inhibitory PI3Kγ offer additional strategy pulmonary diseases.

Язык: Английский

Процитировано

0
Integration of Consensus‐Based Pharmacophore Mapping and Molecular Docking in Sequential Virtual Screening: Toward the Discovery of Novel PI3Kγ Inhibitors DOI

X Yu,

Shiru Yuan,

Lei Jia

и другие.

ChemistrySelect, Год журнала: 2024, Номер 9(41)

Опубликована: Окт. 28, 2024

Abstract Numerous research studies have demonstrated the significant correlation of phosphatidylinositol‐3 kinase gamma (PI3Kγ) with onset and progression various human diseases, highlighting PI3Kγ as a promising therapeutic target. However, demonstrates considerable similarity other isoforms in PI3K family, presenting challenges creation inhibitors. This study presents an ensemble‐based virtual screening approach to discover novel inhibitors targeting PI3Kγ. Eganelisib (IPI‐549) is sole selective inhibitor that has progressed clinical trials, making it model for advancement Initially, common feature pharmacophore receptor–ligand models were independently developed using IPI‐549 its potent derivatives, conjunction crystal complex PI3Kγ/IPI‐549. Both qualitative proved highly effective at distinguishing between active inactive compounds. Then, four widely utilized docking programs chosen assessment, where Glide_SP mode superior predictive accuracy sampling ligand conformations during binding, effectively noninhibitors. Finally, protocol was conducted screen ChEMBL database, utilizing search, consensus‐based mapping, sequential molecular docking. process resulted identification multiple molecules exhibiting notable promise

Язык: Английский

Процитировано

0