Identification of “Preferred” Human Kinase Inhibitors for Sleeping Sickness Lead Discovery. Are Some Kinases Better than Others for Inhibitor Repurposing?

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.

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Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

Nature Chemistry ◽

10.1038/s41557-019-0378-7 ◽

2019 ◽

Vol 12 (2) ◽

pp. 145-158 ◽

Cited By ~ 13

Author(s):

Philipp Le ◽

Elena Kunold ◽

Robert Macsics ◽

Katharina Rox ◽

Megan C. Jennings ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Kinase Inhibitors ◽

Drug Resistant ◽

Human Kinase

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Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases

ChemMedChem ◽

10.1002/cmdc.201700259 ◽

2017 ◽

Vol 12 (16) ◽

pp. 1235-1253 ◽

Cited By ~ 16

Author(s):

Maria Dichiara ◽

Agostino Marrazzo ◽

Orazio Prezzavento ◽

Simona Collina ◽

Antonio Rescifina ◽

...

Keyword(s):

Kinase Inhibitors ◽

Human Kinase

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Are immune checkpoint combination therapies for intermediate and poor risk renal cell carcinoma better than immune checkpoint inhibitors combined with kinase inhibitors?

The Lancet Oncology ◽

10.1016/s1470-2045(21)00130-3 ◽

2021 ◽

Vol 22 (5) ◽

pp. 593-594

Author(s):

David F McDermott ◽

Michael B Atkins ◽

Brian I Rini

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Combination Therapies ◽

Poor Risk ◽

Better Than

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Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2021.116437 ◽

2021 ◽

Vol 49 ◽

pp. 116437

Author(s):

Pearly Shuyi Ng ◽

Klement Foo ◽

Sandra Sim ◽

Gang Wang ◽

Chuhui Huang ◽

...

Keyword(s):

Kinase Inhibitors ◽

Lead Discovery

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BCR-ABL1 Transcript Levels at 3 and 6 Months Are Better for Identifying Chronic Myeloid Leukemia Patients with Poor Outcome in Response to Second-Line Second-Generation Tyrosine Kinase Inhibitors after Imatinib Failure: A Report from a Single Institution

Acta Haematologica ◽

10.1159/000430835 ◽

2015 ◽

Vol 134 (4) ◽

pp. 248-254 ◽

Cited By ~ 4

Author(s):

Beatriz Felicio Ribeiro ◽

Bruna Rocha Vergílio ◽

Eliana Cristina Martins Miranda ◽

Maria Helena Almeida ◽

Marcia Torresan Delamain ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Second Line ◽

Second Line Therapy ◽

Free Survival ◽

Transcript Levels ◽

Real Time Quantitative Pcr ◽

Better Than

Early reduction of BCR-ABL1 transcript levels has been associated with improved outcome in chronic myeloid leukemia (CML) treatment. We evaluated 54 chronic-phase CML patients treated with imatinib who switched therapy to dasatinib (n = 33) or nilotinib (n = 21). BCR-ABL1 transcript levels were measured in peripheral blood using real-time quantitative PCR (RQ-PCR) every 3 months from the start of second-line treatment. Patients with BCR-ABL transcript levels >10% at 3 months and >1% at 6 months had significantly inferior progression-free (PFS) and event-free survival (EFS) than patients with RQ-PCR <10% at 3 months and <1% at 6 months (66 vs. 100%, p = 0.01, and 33 vs. 73%, p = 0.02, respectively). Patients with RQ-PCR <10% at 3 months and >1% at 6 months also had inferior PFS and EFS than patients with RQ-PCR <10% at 3 months and <1% at 6 months (48 vs. 100%, p = 0.002, and 25 vs. 73%, p < 0.0001, respectively). Two measurements of BCR-ABL levels were better than a single one to stratify chronic-phase CML patients as failure after second-line therapy.

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First Cdc7 Kinase Inhibitors: Pyrrolopyridinones as Potent and Orally Active Antitumor Agents. 2. Lead Discovery

Journal of Medicinal Chemistry ◽

10.1021/jm9000506 ◽

2009 ◽

Vol 52 (4) ◽

pp. 1230-1230

Author(s):

Maria Menichincheri ◽

Alberto Bargiotti ◽

Jens Berthelsen ◽

Jay A. Bertrand ◽

Roberto Bossi ◽

...

Keyword(s):

Kinase Inhibitors ◽

Antitumor Agents ◽

Lead Discovery ◽

Cdc7 Kinase ◽

Orally Active

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An evaluation of combined strategies for improving the performance of molecular docking

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720021500037 ◽

2021 ◽

pp. 2150003

Author(s):

Siqi Xu ◽

Li Wang ◽

Xianchao Pan

Keyword(s):

Molecular Docking ◽

Binding Mode ◽

Computational Method ◽

Scoring Functions ◽

Lead Discovery ◽

Power Test ◽

High Quality Protein ◽

Docking Program ◽

Better Than ◽

Docking Power

Molecular docking is a fast and efficient computational method for the prediction of the binding mode and binding affinity between a ligand and a target protein at the atomic level. However, the performance of current docking programs is less than satisfactory. Herein, with a focus on free programs and scoring functions, the performances of LeDock and three standalone scoring functions were tested by 195 high-quality protein–ligand complexes. Results showed that the success rate for the best pose of the free available docking program LeDock achieved 89.20%, indicative of a strong sampling power. Based on the poses generated by LeDock, a comparative evaluation on other three non-commercial scoring functions, including DSX (DrugScore X), PoseScore and X-score was performed. Among all the evaluated scoring functions, DSX and X-score exhibited the best scoring power and ranking power, respectively. The performances of LeDock, DSX and X-score were similar in docking power test, which was much better than the PoseScore. Accordingly, it was suggested that the combination of pose sampling by LeDock with rescoring by DSX or X-score could improve the prediction accuracy of molecular docking and applied in the lead discovery.

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THP-1 and Dictyostelium Infection Models for Screening and Characterization of Anti-Mycobacterium abscessus Hit Compounds

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01601-19 ◽

2019 ◽

Vol 64 (1) ◽

Cited By ~ 2

Author(s):

Adrian Richter ◽

Tirosh Shapira ◽

Yossef Av-Gay

Keyword(s):

Host Cell ◽

Kinase Inhibitors ◽

Screening Method ◽

Inhibitory Effect ◽

Mycobacterium Abscessus ◽

Infection Model ◽

Content Type ◽

Human Macrophages ◽

Human Kinase ◽

Mycobacterial Growth

ABSTRACT !!NCR1!! presents a great challenge to antimycobacterial therapy due to its innate resistance against most antibiotics. M. abscessus is able to grow intracellularly in human macrophages, suggesting that intracellular models can facilitate drug discovery. Thus, we have developed two host cell models: human macrophages for use in a new high-content screening method for M. abscessus growth and a Dictyostelium discoideum infection model with the potential to simplify downstream genetic analysis of host cell factors. A screen of 568 antibiotics for activity against intracellular M. abscessus led to the identification of two hit compounds with distinct growth inhibition. A collection of 317 human kinase inhibitors was analyzed, with the results yielding three compounds with an inhibitory effect on mycobacterial growth, strengthening the notion that host-directed therapy can be applied for M. abscessus.

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