scholarly journals Structure-Based Virtual Screening, Synthesis and Biological Evaluation of Potential FAK-FAT Domain Inhibitors for Treatment of Metastatic Cancer

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3488
Author(s):  
Sahar B. Kandil ◽  
Samuel R. Jones ◽  
Sonia Smith ◽  
Stephen E. Hiscox ◽  
Andrew D. Westwell
Keyword(s):  
Breast Cancer ◽  
Virtual Screening ◽  
Focal Adhesion ◽  
Antiproliferative Activity ◽  
Metastatic Cancer ◽  
Biological Evaluation ◽  
Bt474 Cell ◽  
Pharmacokinetic Studies ◽  
Lead Compound ◽  
Compound I

Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more than 210K compounds against the focal adhesion targeting FAK-focal adhesion targeting (FAT) domain to identify 25 virtual hit compounds which were screened in the invasive breast cancer line (MDA-MB-231). Most notably, compound I showed low micromolar antiproliferative activity, as well as antimigratory activity. Moreover, examination in a model of triple negative breast cancer (TNBC), revealed that, despite not effecting FAK phosphorylation, compound I significantly impairs proliferation whilst impairing focal adhesion growth and turnover leading to reduced migration. Further optimisation and synthesis of analogues of the lead compound I using a four-step synthetic procedure was performed, and analogues were assessed for their antiproliferative activity against three breast cancer (MDA-MB-231, T47D, BT474) cell lines and one pancreatic cancer (MIAPaCa2) cell line. Compound 5f was identified as a promising lead compound with IC50 values in the range of 4.59–5.28 μM in MDA-MB-231, T47D, BT474, and MIAPaCa2. Molecular modelling and pharmacokinetic studies provided more insight into the therapeutic features of this new series.

scholarly journals Discovery of potent human lactate dehydrogenase A (LDHA) inhibitors with antiproliferative activity against lung cancer cells: virtual screening and biological evaluation

MedChemComm ◽  
2017 ◽  
Vol 8 (3) ◽  
pp. 599-605 ◽  
Author(s):  
Xiao-Mei Li ◽  
Wen-Hua Xiao ◽  
Hui-Xia Zhao
Keyword(s):  
Lung Cancer ◽  
Lactate Dehydrogenase ◽  
Virtual Screening ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Biological Evaluation ◽  
Lung Cancer Cells ◽  
Inhibitory Potency

A novel inhibitor with good inhibitory potency (IC50 = 0.36 μM) against LDHA that inhibits the growth of A549 and NCI-H1975 lung cancer cells was reported herein.

scholarly journals Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3499
Author(s):  
Svetlana K. Vorontsova ◽  
Anton V. Yadykov ◽  
Alexander M. Scherbakov ◽  
Mikhail E. Minyaev ◽  
Igor V. Zavarzin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antiproliferative Activity ◽  
Chloride Ion ◽  
Biological Evaluation ◽  
Breast Cancer Cell Lines ◽  
X Ray Diffraction ◽  
Single Diastereomer ◽  
Scale Experiment ◽  
Synthesis And Biological Evaluation ◽  
Mcf 7

The acid-catalyzed cyclization of benzylidenes based on 16-dehydropregnenolone acetate (16-DPA) was studied. It was found that these compounds readily undergo regioselective interrupted Nazarov cyclization with trapping chloride ion and an efficient method of the synthesis of d-annulated pentacyclic steroids based on this reaction was proposed. The structures of the synthesized pentacyclic steroids were determined by NMR and X-ray diffraction. It was found that the reaction affords a single diastereomer, but the latter can crystallize as two conformers depending on the structure. Antiproliferative activity of synthesized compounds was evaluated against two breast cancer cell lines: MCF-7 and MDA-MB-231. All tested compounds showed relatively high antiproliferative activity. The synthetic potential of the protocol developed was illustrated by the gram-scale experiment.

Design, Synthesis and Biological Evaluation of Uracil Derivatives as Novel VEGFR-2 Inhibitors

2018 ◽  
Vol 24 (6) ◽  
pp. 734-740 ◽  
Author(s):  
Jingwei Liang ◽  
Xinyang Li ◽  
Su Yang ◽  
Xin He ◽  
Mingyang Wang ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Screening Method ◽  
Growth Factor Receptor ◽  
Biological Evaluation ◽  
Type I ◽  
Lead Compound ◽  
Design Synthesis ◽  
Uracil Derivatives ◽  
Inhibitory Activities

Backgound: Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. Type I inhibitors constitute the major ATP-competitive inhibitors and recognize mainly the active conformation of VEGFR-2. Meanwhile, type II inhibitors recognize the inactive DFG (Asp- Phe-Gly)-out conformation of VEGFR-2, which was a more promising approach for drug intervention. Methods: According to the lead compound of uracil skeleton, being screened out by structure-based virtual screening, a series of uracil derivatives were designed and synthesized. Results: The inhibitory activities were investigated against VEGFR-2 kinase in vitro. The results turned out that series A performed moderate inhibitory activities, especially compound A4 exhibited the most potent inhibitory activity (IC50=0.029 µM). Conclusion: The lead compound was screened out by structure-based pharmacophore models, then two series of uracil derivatives were synthesized according to it and evaluated for their inhibitory activities against VEGFR-2. In this study, not only a potential inhibitor has been discovered, it also demonstrates the feasibility of structure-based virtual screening method for drug discovery.

Synthesis and Biological Evaluation of Oxopyrido[2,3-d] Pyrimidine-7- ones Derivatives as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

2019 ◽  
Vol 16 (8) ◽  
pp. 826-834
Author(s):  
Ao Niu ◽  
Yang Wang ◽  
Yushe Yang ◽  
Jianhai Wei ◽  
Jian Ding ◽  
...  
Keyword(s):  
Cell Cancer ◽  
Biological Evaluation ◽  
Egfr Inhibitors ◽  
Continuous Treatment ◽  
Pharmacokinetic Studies ◽  
Lead Compound ◽  
Inhibition Assay ◽  
T790m Mutation ◽  
Kinase Inhibition

Background: None small cell cancer (NSCLC) is one of the most common cancer around the globe. First generation EGFR-TKI such as gefitinib and erlotinib are now documentated a prolonged PFS in NSCLC patients with EGFR activating mutation. However, upon continuous treatment, patients become resistant due toCEE T790M mutation in most cases.Second generation covalent EGFR inhibitors like afatinib have a moderate inhibition to EGFRT790M in preclinical models,but it is lacking efficacy in the clinical use for patients with T790M mutation due to the dose-limiting EGFRWT-driven toxicities.Third generation EGFR inhibitors have the potential to overcome EGFRT790M resistance mutations while reducing EGFRWT-driven toxicities and are now under active research. Methods: We took compound 6 as our lead compound. We focused on structural modifications around the hydrophile side chain, the linker, and the Micheal addition receptor moiety of AMG. A novel series of Oxopyrido[2,3-d]pyrimidine-7-ones derivatives have been designed and synthesized. Their kinase inhibition activity against EGFRWT and EGFRL858R/T790M were tested by ELISA assays. SRB test was used for cellular anti-proliferation evaluation. Results: A total of 21 novel Oxopyrido[2,3-d]pyrimidine-7-ones derivatives have been designed and synthesized. The compounds were characterized with 1H-NMR and HRMS. Their structureactivity relationships have been preliminaryly investigated. As a result, compound 7k showed comparable activity in kinase inhibition assay and cell growth inhibition assay with our lead compound 6. Higher activity and selectivity over EGFRWT were observed in the in vitro antitumour assay comparing compound 7k to AZD-9291. Compound 7a exhibited higher selectivity over EGFRWT in kinase inhibition assay, but poor cell inhibition to NCI-1975 cell line. The in vivo pharmacokinetic studies in rats showed that compound 9a exhibited improved pharmacokinetic profiles comparing to 6. Compound 9a was also efficacious in an NCI-H1975 murine xenograft model 30 mg/kg QD. Conclusion: Compound 9a has a potent kinase inhibition to EGFRT790M and has a high selectivity over EGFRWT. It’s also efficacious in an in vivo pharmacodynamic evaluation assay. Significant advantages were observed in pharmacokinetic evaluation comparing 9a to 6, which provide us a reference to further drug design and research.

3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity

2017 ◽  
Vol 20 (4) ◽  
Author(s):  
Jelena Oluić ◽  
Katarina Nikolic ◽  
Jelica Vucicevic ◽  
Zarko Gagic ◽  
Slavica Filipic ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Antiproliferative Activity ◽  
Mtor Inhibitors ◽  
3D Qsar

Design, Synthesis and Biological Evaluation of 3-(3,4,5-Trimethoxyphenyl)- 5-(2-(5-arylbenzo[b]thiophen-3-yl)oxazol-5-yl)isoxazole Derivatives as Anticancer Agents

2020 ◽  
Vol 17 (5) ◽  
pp. 345-351
Author(s):  
Syndla Premalatha ◽  
G. Rambabu ◽  
Islavathu Hatti ◽  
Dittakavi Ramachandran
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Isoxazole Derivatives

A new series of 3-(3,4,5-trimethoxyphenyl)-5-(2-(5-arylbenzo[b]thiophen-3-yl)oxa zol-5- yl)isoxazole derivatives were designed and synthesized. All these derivatives were evaluated for their anticancer activity against various human cancer cell lines such as MCF-7 (breast cancer), A549 (lung cancer), DU-145 (prostate cancer) and MDA MB-231 (breast cancer)-four human cancer cell lines by using MTT assay. Here, etoposide was used as a standard reference drug and most of the compounds were exhibited good anticancer activity with respect to cell lines. Among all compounds, five compounds 11b, 11c, 11f, 11i and 11j showed more potent activity than standard drug, in which, compound 11f was the most promising compound.

Machine Learning-based Virtual Screening Strategy Reveals Some Natural Compounds As Potential PAK4 Inhibitors In Triple Negative Breast Cancer

2020 ◽  
Vol 18 ◽  
Author(s):  
Opeyemi Iwaloye ◽  
Olusola Olalekan Elekofehinti ◽  
Babatomiwa Kikiowo ◽  
Emmanuel Ayo Oluwarotimi ◽  
Toyin Mary Fadipe
Keyword(s):  
Breast Cancer ◽  
Virtual Screening ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Energy Calculation ◽  
Reference Drug ◽  
Predictive Quality

Background: P-21 activating kinase 4 (PAK4) is implicated in poor prognosis of many cancers, especially in the progression of Triple Negative Breast Cancer (TNBC). The present study was aimed at designing some potential drug candidates as PAK4 inhibitors for breast cancer therapy. Objective: This study aimed to finding novel inhibitors of PAK4 from natural compounds using computational approach. Methods: An e-pharmacophore model was developed from docked PAK4-coligand complex and used to screen over a thousand natural compounds downloaded from BIOFACQUIM and NPASS databases to match a minimum of 5 sites for selected (ADDDHRR) hypothesis. The robustness of the virtual screening method was accessed by well-established methods including EF, ROC, BEDROC, AUAC, and the RIE. Compounds with fitness score greater than one were filtered by applying molecular docking (HTVS, SP, XP and Induced fit docking) and ADME prediction. Using Machine learningbased approach QSAR model was generated using Automated QSAR. The computed top model kpls_des_17 (R2= 0.8028, RMSE = 0.4884 and Q2 = 0.7661) was used to predict the pIC50 of the lead compounds. Internal and external validations were accessed to determine the predictive quality of the model. Finally the binding free energy calculation was computed. Results: The robustness/predictive quality of the models were affirmed. The hits had better binding affinity than the reference drug and interacted with key amino acids for PAK4 inhibition. Overall, the present analysis yielded three potential inhibitors that are predicted to bind with PAK4 better than reference drug tamoxifen. The three potent novel inhibitors vitexin, emodin and ziganein recorded IFD score of -621.97 kcal/mol, -616.31 kcal/mol and -614.95 kcal/mol, respectively while showing moderation for ADME properties and inhibition constant. Conclusion: It is expected that the findings reported in this study may provide insight for designing effective and less toxic PAK4 inhibitors for triple negative breast cancer.

scholarly journals The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

Oncogene ◽  
2021 ◽  
Author(s):  
Qiuping Xu ◽  
Jingwei Zhang ◽  
Brian A. Telfer ◽  
Hao Zhang ◽  
Nisha Ali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Tumor Growth ◽  
Focal Adhesion ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Adhesion Protein ◽  
Focal Adhesion Protein

AbstractThere is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.

Sign in / Sign up

Export Citation Format

Share Document