scholarly journals Computational evaluation of potent 2-(1H-imidazol-2-yl) pyridine derivatives as potential V600E-BRAF inhibitors

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Abdullahi Bello Umar ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Docking Studies ◽  
Major Protein ◽  
Pharmacological Properties ◽  
Braf Inhibitors ◽  
Protein Target ◽  
Computational Evaluation ◽  
Better Than

Abstract Background V600E-BRAF is a major protein target involved in various types of human cancers. However, the acquired resistance of the V600E-BRAF kinase to the vemurafenib and the side effects of other identified drugs initiate the search for efficient inhibitors. In the current paper, virtual docking screening combined with drug likeness and ADMET properties predictions were jointly applied to evaluate potent 2-(1H-imidazol-2-yl) pyridines as V600E-BRAF kinase inhibitors. Results Most of the studied compounds showed better docking scores and favorable interactions with theiV600E-BRAF target. Among the screened compounds, the two most potent (14 and 30) with good rerank scores (−124.079 and − 122.290) emerged as the most effective, and potent V600E-BRAF kinase inhibitors which performed better than vemurafenib (−116.174), an approved V600E-BRAF kinase inhibitor. Thus, the docking studies exhibited that these compounds have shown competing inhibition of V600E-BRAF kinase with vemurafenib at the active site and revealed better pharmacological properties based on Lipinski’s and Veber’s drug-likeness rules for oral bioavailability and ADMET properties. Conclusion The docking result, drug-likeness rules, and ADMET parameters identified compounds (14 and 30) as the best hits against V600E-BRAF kinase with better pharmacological properties. This suggests that these compounds may be developed as potent V600E-BRAF inhibitors.

scholarly journals In silico evaluation of some 4-(quinolin-2-yl)pyrimidin-2-amine derivatives as potent V600E-BRAF inhibitors with pharmacokinetics ADMET and drug-likeness predictions

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Abdullahi Bello Umar ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Molecular Docking ◽  
Side Effects ◽  
Oral Bioavailability ◽  
In Silico ◽  
Braf Inhibitor ◽  
Docking Studies ◽  
Pharmacological Properties ◽  
Braf Inhibitors ◽  
Docking Analysis ◽  
Risk Parameters

Abstract Background The resistance of V600E-BRAF to the vemurafenib and the side effects of the identified inhibitors trigger the research for a novel and more potent anti-melanoma agents. In this study, virtual docking screening along with pharmacokinetics ADMET and drug-likeness predictions were combined to evaluate some 4-(quinolin-2-yl)pyrimidin-2-amine derivatives as potent V600E-BRAF inhibitors. Results Some of the selected compounds exhibited better binding scores and favorable interaction with the V600E-BRAF enzyme. Out of the screened compounds, two most potent (5 and 9) having good Rerank scores (− 128.011 and − 126.258) emerged as effective and potent V600E-BRAF inhibitors that outperformed the FDA-approved V600E-BRAF inhibitor (vemurafenib, − 118.607). Thus, the molecular docking studies revealed that the studied compounds showed competing for inhibition of V600E-BRAF with vemurafenib at the binding site and possessed better pharmacological parameters based on the drug-likeness rules filters for the oral bioavailability, and ADMET risk parameters. Conclusion The docking analysis, drug-likeness rules filters, and ADMET study identified compounds (5 and 9) as the best hits against V600E-BRAF kinase with enhanced pharmacological properties. This recommends that these compounds may be developed as potent anti-melanoma agents.

scholarly journals Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2394
Author(s):  
Donatella Romaniello ◽  
Ilaria Marrocco ◽  
Nishanth Belugali Nataraj ◽  
Irene Ferrer ◽  
Diana Drago-Garcia ◽  
...  
Keyword(s):  
Drug Target ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Underlying Mechanism ◽  
Xenograft Models ◽  
Emergence Of Resistance ◽  
Egfr Kinase ◽  
Egfr Antibody

Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensatory up-regulation of HER3 and several secreted forms, we anticipated that blocking HER3 would prevent resistance. As demonstrated herein, a neutralizing anti-HER3 antibody we generated can clear HER3 from the cell surface, as well as reduce HER3 cleavage by ADAM10, a surface metalloproteinase. When combined with a kinase inhibitor and an anti-EGFR antibody, the antibody completely blocked patient-derived xenograft models that acquired resistance to EGFRi. We found that the underlying mechanism involves posttranslational downregulation of HER3, suppression of MET and AXL upregulation, as well as concomitant inhibition of AKT signaling and upregulation of BIM, which mediates apoptosis. Thus, although HER3 is nearly devoid of kinase activity, it can still serve as an effective drug target in the context of acquired resistance. Because this study simulated in animals the situation of patients who develop resistance to EGFRi and remain with no obvious treatment options, the observations presented herein may warrant clinical testing.

scholarly journals Profiling of the drug resistance of thousands of Src tyrosine kinase mutants uncovers a regulatory network that couples autoinhibition to the dynamics of the catalytic domain

2021 ◽  
Author(s):  
Sujata Chakraborty ◽  
Ethan Ahler ◽  
Jessica J. Simon ◽  
Linglan Fang ◽  
Zachary E. Potter ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Catalytic Domain ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Protein Kinase Inhibitors ◽  
Resistance Mutations ◽  
Src Tyrosine Kinase ◽  
Inhibitor Resistance

SUMMARYProtein kinase inhibitors are effective cancer therapies, but acquired resistance often limits clinical efficacy. Despite the cataloguing of numerous resistance mutations with model studies and in the clinic, we still lack a comprehensive understanding of kinase inhibitor resistance. Here, we measured the resistance of thousands of Src tyrosine kinase mutants to a panel of ATP-competitive inhibitors. We found that ATP-competitive inhibitor resistance mutations are distributed throughout Src’s catalytic domain. In addition to inhibitor contact residues, residues that participate in regulating Src’s phosphotransferase activity were prone to the development of resistance. Unexpectedly, a resistance-prone cluster of residues that are on the top face of the N-terminal lobe of the catalytic domain contributes to Src autoinhibition by reducing the dynamics of the catalytic domain, and mutations in this cluster led to resistance by lowering inhibitor affinity and promoting kinase hyperactivation. Together, our studies demonstrate how comprehensive profiling of drug resistance can be used to understand potential resistance pathways and uncover new mechanisms of kinase regulation.

EGFR-A763_Y764insFQEA: A unique exon 20 insertion mutation that displays sensitivity to all classes of approved lung cancer EGFR tyrosine kinase inhibitors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20593-e20593 ◽  
Author(s):  
Carol Gergis ◽  
Deepa Rangachari ◽  
Masanori Fujii ◽  
Andreas Varkaris ◽  
Paul A VanderLaan ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Insertion Mutation ◽  
Preclinical Models ◽  
Lung Cancers ◽  
Egfr Tyrosine Kinase ◽  
Exon 20 ◽  
Egfr Tkis

e20593 Background: The epidermal growth factor receptor (EGFR)-A763_Y764insFQEA mutation is a unique exon 20 insertion mutation (accounting for ~10-20% of all EGFR exon 20 insertions) that more closely resembles EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutants (i.e. EGFR-exon 19 deletions and L858R) at the structural and enzymatic level as compared to other non-classical mutations. A limited number of preclinical models and clinical reports have detailed the response of EGFR-A763_Y764insFQEA-driven lung tumors to approved or in-development TKIs. Methods: Multiple preclinical models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations were used to probe representative 1st generation (gefitinib, erlotinib), 2nd generation (afatinib, dacomitinib), 3rd generation (osimertinib), and in-development EGFR exon 20 specific (poziotinib, others) TKIs. Clinical outcomes and prior reports of EGFR-A763_Y764insFQEA mutated lung adenocarcinomas treated with EGFR TKIs were compiled. Results: Cell lines driven by EGFR-A763_Y764insFQEA were consistently sensitive to 1st, 2nd and 3rd generation EGFR TKIs, while models driven by other EGFR exon 20 insertions (i.e. D770_N771insSVD and H773_V774insH) were only inhibited by in-development EGFR TKIs and at doses below those affecting the wild-type receptor. The majority of patients with lung cancers harboring EGFR-A763_Y764insFQEA responded to clinical doses of 1st, 2nd, and 3rd generation EGFR TKIs; and lung cancers with these mutants are currently enrolled in clinical trials of in-development EGFR exon 20 specific TKIs. Conclusions: This is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is a unique exon 20 insertion mutation sensitive to 1st, 2nd, 3rd generation and in-development EGFR exon 20 specific TKIs. Mechanisms of acquired resistance of this mutant to different EGFR TKIs remain unreported.

scholarly journals Treating Imatinib-Resistant Leukemia: The Next Generation Targeted Therapies

2006 ◽  
Vol 6 ◽  
pp. 918-930 ◽  
Author(s):  
Michael R. Burgess ◽  
Charles L. Sawyers
Keyword(s):  
Signaling Pathways ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Clinical Success ◽  
Hypereosinophilic Syndrome ◽  
Acquired Resistance ◽  
Kinase Domain ◽  
Imatinib Resistance ◽  
Sti 571 ◽  
Clinical Resistance

Imatinib (Gleevec/STI-571/CGP57148B, Novartis) is a small-molecule, tyrosine kinase inhibitor developed to target BCR-ABL, c-Kit, and PDGF-R. Through inhibition of these oncogenic kinases, imatinib is effective in the treatment of BCR-ABL–positive leukemia, gastrointestinal stromal tumor, and hypereosinophilic syndrome, respectively. However, clinical success of imatinib is hampered by acquired resistance that may occur through several mechanisms including kinase domain mutation, target amplification, and activation of alternate signaling pathways. Strategies to overcome resistance have included targeting BCR-ABL stability and downstream signaling pathways important for tumor growth. Additional work has shown that new BCR-ABL kinase inhibitors with increased potency or alternate conformation-binding properties can target imatinib resistance. This review focuses on the mechanisms of imatinib resistance and the strategies currently being developed to overcome clinical resistance.

scholarly journals Reactive Oxygen Species (ROS)-Sensitive Prodrugs of the Tyrosine Kinase Inhibitor Crizotinib

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1149 ◽  
Author(s):  
Bjoern Bielec ◽  
Isabella Poetsch ◽  
Esra Ahmed ◽  
Petra Heffeter ◽  
Bernhard K. Keppler ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Culture Medium ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Docking Studies ◽  
Binding Ability ◽  
Human Lung Fibroblast ◽  
Activation Behavior

Tyrosine kinase inhibitors revolutionized cancer therapy but still evoke strong adverse effects that can dramatically reduce patients’ quality of life. One possibility to enhance drug safety is the exploitation of prodrug strategies to selectively activate a drug inside the tumor tissue. In this study, we designed a prodrug strategy for the approved c-MET, ALK, and ROS1 tyrosine kinase inhibitor crizotinib. Therefore, a boronic-acid trigger moiety was attached to the 2-aminopyridine group of crizotinib, which is a crucial position for target kinase binding. The influence of the modifications on the c-MET- and ALK-binding ability was investigated by docking studies, and the strongly reduced interactions could be confirmed by cell-free kinase inhibition assay. Furthermore, the newly synthesized compounds were tested for their activation behavior with H2O2 and their stability in cell culture medium and serum. Finally, the biological activity of the prodrugs was investigated in three cancer cell lines and revealed a good correlation between activity and intrinsic H2O2 levels of the cells for prodrug A. Furthermore, the activity of this prodrug was distinctly reduced in a non-malignant, c-MET expressing human lung fibroblast (HLF) cell line.

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