Thiazolidinedione‐Based PI3Kα Inhibitors: An Analysis of Biochemical and Virtual Screening Methods

Pinson, Jo‐Anne; Schmidt‐Kittler, Oleg; Zhu, Jianhua; Jennings, Ian G.; Kinzler, Kenneth W.; Vogelstein, Bert; Chalmers, David K.; Thompson, Phillip E.

doi:10.1002/cmdc.201000467

Cited by 16 publications

(9 citation statements)

References 71 publications

(143 reference statements)

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“…27,28 Among these residues, Asp933 was considered to be the most important. 29 Our docking studies appeared to confirm this observation. The corresponding position (Gln859 of PI3Kα) in PI3Kc is Lys890.…”

supporting

confidence: 62%

Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases

Sabbah

Simms

Brattain

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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The alpha isoform of the phosphatidylinositol-3-kinases (PI3Kα) is often mutated, amplified and overex-pressed in human tumors. In an effort to develop new inhibitors targeting this enzyme, we carried out a pharmacophore model study based on six PI3Kα-selective compounds. The pharmacophore searching identified three structurally novel inhibitors of PI3Kα and its H1047R mutant. Our biological studies show that two of our hit molecules suppressed the formation of pAKT, a downstream effector of PI3Kα, and induced apoptosis in the HCT116 colon cancer cell line. QPLD-based docking showed that residues Asp933, Glu849, Val851, and Gln859 appeared to be key binding residues for active inhibitors.

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supporting

confidence: 62%

Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases

Sabbah

Simms

Brattain

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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“…Among these strategies, except for VS, all other methods require most advanced techniques and equipments, such as robotic facility, high resolution of fluorescent microscopes, and mass spectrometers, which are very cost and time-consuming. In contrast, by taking advantage of the in-depth understanding of the crystal structure, the molecular mechanism of known PI3K inhibitors, the advancement of molecular docking, and the availability of the large small chemicals libraries, VS is therefore regarded as a reliable, cost-effective and time-saving method to identify PI3K inhibitors [ 33 , 34 ]. By using the Glide HTVS coupled SP-XP mode, C98 was identify as a specific inhibition of PI3K enzymes.…”

Section: Discussionmentioning

confidence: 99%

A novel PI3K inhibitor PIK-C98 displays potent preclinical activity against multiple myeloma

Zhu

Wang

et al. 2014

Oncotarget

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Recent clinical trials have demonstrated targeting PI3K pathway is a promising strategy for the treatment of blood cancers. To identify novel PI3K inhibitors, we performed a high throughput virtual screen and identified several novel small molecule compounds, including PIK-C98 (C98). The cell-free enzymatic studies showed that C98 inhibited all class I PI3Ks at nano- or low micromolar concentrations but had no effects on AKT or mTOR activity. Molecular docking analysis revealed that C98 interfered with the ATP-binding pockets of PI3Ks by forming H-bonds and arene-H interactions with specific amino acid residues. The cellular assays demonstrated that C98 specifically inhibited PI3K/AKT/mTOR signaling pathway, but had no effects on other kinases and proteins including IGF-1R, ERK, p38, c-Src, PTEN, and STAT3. Inhibition of PI3K by C98 led to myeloma cell apoptosis. Furthermore, oral administration of C98 delayed tumor growth in two independent human myeloma xenograft models in nude mice but did not show overt toxicity. Pharmacokinetic analyses showed that C98 was well penetrated into myeloma tumors. Therefore, through a high throughput virtual screen we identified a novel PI3K inhibitor that is orally active against multiple myeloma with great potential for further development.

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“…Another interesting class of heterocyclic compounds is 5-(1H-Indol-3-ylmethylene) -2thioxothiazolidin-4-ones with wide spectrum of biological activities as well. Among them are antitumor [26,27] and antimicrobial [28,29], inhibitors of proteases anthrax lethal factor, inhibitors against neurotoxin type A [28], aldose reductase [30], PIM kinase [31], PI3Kα [32], IKKβ [33], and GSK-3 [34] enzymes.…”

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confidence: 99%

5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)alkancarboxylic Acids as Antimicrobial Agents: Synthesis, Biological Evaluation, and Molecular Docking Studies

Horishny

Карцев²,

Geronikaki

et al. 2020

Molecules

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Background: Infectious diseases symbolize a global consequential strain on public health security and impact on the socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in crucial need for the discovery and development of novel entity for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using classical methods of organic synthesis. Results: All 20 synthesized compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species. It should be mentioned that all compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Furthermore, 18 compounds appeared to be more potent than streptomycin against Staphylococcus aureus, Enterobacter cloacae, Pseudomonas aeruginosa, Listeria monocytogenes, and Escherichia coli. Three the most active compounds 4h, 5b, and 5g appeared to be more potent against MRSA than ampicillin, while streptomycin did not show any bactericidal activity. All three compounds displayed better activity also against resistant strains P. aeruginosa and E. coli than ampicillin. Furthermore, all compounds were able to inhibit biofilm formation 2-to 4-times more than both reference drugs. Compounds were evaluated also for their antifungal activity against eight species. The evaluation revealed that all compounds exhibited antifungal activity better than the reference drugs bifonazole and ketoconazole. Molecular docking studies on antibacterial and antifungal targets were performed in order to elucidate the mechanism of antibacterial activity of synthesized compounds. Conclusion: All tested compounds showed good antibacterial and antifungal activity better than that of reference drugs and three the most active compounds could consider as lead compounds for the development of new more potent agents.

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Thiazolidinedione‐Based PI3Kα Inhibitors: An Analysis of Biochemical and Virtual Screening Methods

Cited by 16 publications

References 71 publications

Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases

Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases

A novel PI3K inhibitor PIK-C98 displays potent preclinical activity against multiple myeloma

5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)alkancarboxylic Acids as Antimicrobial Agents: Synthesis, Biological Evaluation, and Molecular Docking Studies

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