New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound

Yang, Xiuyan; Zhang, Xi; Huang, Min; Song, Kun; Xuefen, Li; Huang, Meilang; Meng, Linghua; Zhang, Jian

doi:10.1038/s41598-017-15260-5

Cited by 10 publications

(6 citation statements)

References 42 publications

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“…Based on the literature survey, we defined our systematic study to explore the structural scaffolding of the proposed streptenol derivatives. Streptomyces misionensis-BAT-10-03-123, marine-derived bacterium-based stretenol derivatives were tested in cell lines and revealed anticancer activity [ 15 ] PI3K elevated activity is often associated with various human cancers and anticancer drug resistance [ 16 , 17 ]. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) complexed with alpelisib and the receptor-based pharmacophore model were employed for further virtual screening of the streptenol derivatives as inhibitors for PIK3CA.…”

Section: Introductionmentioning

confidence: 99%

Targeting Streptomyces-Derived Streptenol Derivatives against Gynecological Cancer Target PIK3CA: An In Silico Approach

Christy

Vasudevan

Sudha

et al. 2022

BioMed Research International

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Streptomyces is amongst the most amenable genera for biotechnological applications, and it is extensively used as a scaffold for drug development. One of the most effective therapeutic applications in the treatment of cancer is targeted therapy. Small molecule therapy is one of them, and it has gotten a lot of attention recently. Streptomyces derived compounds namely streptenols A, C, and F–I and streptazolin were subjected for ADMET property assessment. Our computational studies based on molecular docking effectively displayed the synergistic effect of streptomyces-derived compounds on the gynecological cancer target PIK3CA. These compounds were observed with the highest docking scores as well as promising intermolecular interaction stability throughout the molecular dynamic simulation. Molecular docking and molecular dynamic modeling techniques were utilized to investigate the binding mode stability of drugs using a pharmacophore scaffold, as well as physicochemical and pharmacokinetic aspects linked to alpelisib. With a root mean square fluctuation of the protein backbone of less than 0.7 nm, they demonstrated a steady binding mode in the target binding pocket. They have also prompted hydrogen bonding throughout the simulations, implying that the chemicals have firmly occupied the active site. A comprehensive study showed that streptenol D, streptenol E, streptenol C, streptenol G, streptenol F, and streptenol B can be considered as lead compounds for PIK3CA-based inhibitor design. To warrant the treatment efficacy against cancer, comprehensive computational research based on proposed chemicals must be assessed through in vitro studies.

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Section: Introductionmentioning

confidence: 99%

Targeting Streptomyces-Derived Streptenol Derivatives against Gynecological Cancer Target PIK3CA: An In Silico Approach

Christy

Vasudevan

Sudha

et al. 2022

BioMed Research International

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“…In brief, cells seeded in 96‐well plates were treated with test compounds in triplicate for 72 hr (Hou et al., ). The OD value was measured at 560 nM with a multiwall spectrophotometer (VersaMax), and the IC 50 values were determined by a four‐parameter logit method of the curve‐fitting program from SoftMax Pro Software (version 5.4.1, Molecular Devices, Menlo Park, CA) (Yang et al., ; Zhao et al., ).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were harvested and subjected to standard Western blot analysis using antibodies against phosphorylated AKT at Ser473 and total AKT (Cell Signaling Technology). β‐actin (Sigma‐Aldrich) was used as a loading control (Yang et al., ; Zhao et al., ).…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis, and biological evaluation of thieno[3,2‐d]pyrimidine derivatives as potential simplified phosphatidylinositol 3‐kinase alpha inhibitors

et al. 2019

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A series of thieno[3,2‐d]pyrimidine derivatives as phosphatidylinositol 3‐kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21. Determination of a co‐crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments.

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“…In some cancers, this catalytic subunit undergoes mutation, leading to hyperactivation. Alpelisib inhibits PI3K with high specificity for PI3K p110α (Yang et al, 2017). Alpelisib received USFDA approval on May 24, 2019, and it is the first USFDA‐approved PI3K inhibitor, indicated for the treatment of, in combination with fulvestrant, postmenopausal female and male patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA)–mutated metastatic breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Development of stability‐indicating assay method and liquid chromatography‐quadrupole‐time‐of‐flight mass spectrometry‐based structural characterization of the forced degradation products of alpelisib

Ghanghav,

Chawathe,

Chauthe

et al. 2023

Biomedical Chromatography

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The US Food and Drug Administration and the European Medicines Agency approved alpelisib in 2019 for the treatment of metastatic breast cancer. A thorough literature review revealed that a stability‐indicating analytical method (SIAM) is not available for the quantification of alpelisib and its degradation products (DPs). In this study, per the comprehensive stress study recommended by the International Council for Harmonisation (ICH), alpelisib was exposed to hydrolysis, oxidation, photolysis, and thermal stress. Degradation of the drug was observed under hydrolysis, oxidative, and photolysis conditions, whereas the drug was stable under thermal stress condition. We developed a SIAM for the separation of alpelisib and its major DPs that were formed under different stress conditions. The validation of the developed method was performed per ICH Q2(R1) guidelines. Five DPs were identified and characterized. Structure elucidation of all DPs was performed with the modern characterization tool of liquid chromatography‐quadrupole time‐of‐flight mass spectrometer (LC‐Q‐TOF‐MS/MS). The degradation pathway of the drug and its mechanisms were outlined, and in silico toxicity prediction was performed using the ProTox‐II tool.

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New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound

Cited by 10 publications

References 42 publications

Targeting Streptomyces-Derived Streptenol Derivatives against Gynecological Cancer Target PIK3CA: An In Silico Approach

Targeting Streptomyces-Derived Streptenol Derivatives against Gynecological Cancer Target PIK3CA: An In Silico Approach

Design, synthesis, and biological evaluation of thieno[3,2‐d]pyrimidine derivatives as potential simplified phosphatidylinositol 3‐kinase alpha inhibitors

Development of stability‐indicating assay method and liquid chromatography‐quadrupole‐time‐of‐flight mass spectrometry‐based structural characterization of the forced degradation products of alpelisib

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