scholarly journals Selectivity and Potency of Natural Product Pim Kinase Inhibitors Identified By in Silico Docking

2021 ◽  
Author(s):  
Michael Russell ◽  
Nicholas Fazio ◽  
Jace Webster ◽  
Marc Hansen
Keyword(s):  
In Silico ◽  
Structure Prediction ◽  
Kinase Inhibitors ◽  
Integration Site ◽  
Leukemia Virus ◽  
Protein Translation ◽  
Atp Binding Site ◽  
In Silico Docking ◽  
Proviral Integration Site ◽  
Biochemical Assays

Abstract PIM3 (Proviral Integration site for Maloney murine leukemia virus kinase 3) is a proto-oncogene with serine/threonine kinase activity that prevents apoptosis, promotes cell survival, and stimulates protein translation. Additionally, PIM3 functions in inflammation and immunity pathways. PIM3 inhibitors are being developed to treat cancer and inflammation-related disorders. Here we screen a 98,000 compound virtual library of natural products to identify those that are predicted to fit in the ATP site of PIM3. Since the structure of PIM3 has not been determined experimentally, we performed molecular structure prediction using the SWISS-MODEL tool to generate a PIM3 model structure for in silico screening. Compounds predicted to fit the ATP binding site of PIM3 were validated using biochemical assays, revealing activity against PIM3 for all 8 candidates, with potencies mostly in the micromolar range. We tested several analogs of two validated candidates, the diosgenin glycoside dioscin and the biflavonoid hinokiflavone. Among five dioscin analogs, three exhibit similar potency against PIM3, and with some selectivity for PIM3 versus PIM1 and 2. Meanwhile, 3 of seven biflavonoid analogs exhibit sub-micromolar IC50 potency against PIM3, but with less selectivity for PIM3 versus PIM 1 and 2.

scholarly journals New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 867
Author(s):  
Bruno Oyallon ◽  
Marie Brachet-Botineau ◽  
Cédric Logé ◽  
Thomas Robert ◽  
Stéphane Bach ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Cancer Progression ◽  
Kinase Inhibitors ◽  
Integration Site ◽  
Leukemia Virus ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Proviral Integration Site ◽  
Quinoxaline Derivatives

Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure–activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.

A New Series of Antileukemic Agents: Design, Synthesis, In Vitro and In Silico Evaluation of Thiazole-Based ABL1 Kinase Inhibitors

2020 ◽  
Vol 20 ◽  
Author(s):  
Ebru Zeytün ◽  
Mehlika D. Altıntop ◽  
Belgin Sever ◽  
Ahmet Özdemir ◽  
Doha E. Ellakwa ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Anticancer Activity ◽  
Cell Line ◽  
Antiproliferative Activity ◽  
In Silico ◽  
K562 Cell ◽  
Kinase Inhibitors ◽  
K562 Cell Line ◽  
Cytotoxic Effects ◽  
Atp Binding Site

Background: After the milestone approval of imatinib, more than 25 antitumor agents targeting kinases have been approved, and several promising candidates are in various stages of clinical evaluation. Objectives : Due to the importance of thiazole scaffold in targeted anticancer drug discovery, the goal of this work is the design of new thiazolyl hydrazones as potent ABL1 kinase inhibitors for the management of chronic myeloid leukemia (CML). Methods: New thiazolyl hydrazones (2a-p) were synthesized and investigated for their cytotoxic effects on K562 CML cell line. Compounds 2h, 2j and 2l showed potent anticancer activity against K562 cell line. The cytotoxic effects of these compounds on other leukemia (HL-60, MT-2 and Jurkat) and HeLa human cervical carcinoma cell lines were also investigated. Furthermore, their cytotoxic effects on mitogen-activated peripheral blood mononuclear cells (MA-PBMCs) were evaluated to determine their selectivity. Due to its selective and potent anticancer activity, compound 2j was benchmarked for its apoptosis-inducing potential on K562 cell line and inhibitory effects on eight different tyrosine kinases (TKs) including ABL1 kinase. In order to investigate the binding mode of compound 2j into the ATP binding site of ABL1 kinase (PDB: 1IEP), molecular docking study was conducted using MOE 2018.01 program. The QikProp module of Schrödinger’s Molecular modelling package was used to predict the pharmacokinetic properties of compounds 2a-p. Results: 4-(4-(Methylsulfonyl)phenyl)-2-[2-((1,3-benzodioxol-4-yl)methylene)hydrazinyl]thiazole (2j) showed antiproliferative activity against K562 cell line with an IC50 value of 8.87±1.93 µM similar to imatinib (IC50= 6.84±1.11 µM). Compound 2j was found to be more effective than imatinib on HL-60, Jurkat and MT-2 cells. Compound 2j also showed cytotoxic activity against HeLa cell line similar to imatinib. The higher selectivity index value of compound 2j than imatinib indicated that its antiproliferative activity was selective. Compound 2j also induced apoptosis in K562 cell line more than imatinib. Among eight TKs, compound 2j showed the strongest inhibitory activity against ABL1 kinase enzyme (IC50= 5.37±1.17 µM). According to molecular docking studies, compound 2j exhibited high affinity to the ATP binding site of ABL1 kinase forming significant intermolecular interactions. On the basis of in silico studies, this compound did not violate Lipinski's rule of five and Jorgensen's rule of three. Conclusion: Compound 2j stands out as a potential orally bioavailable ABL1 kinase inhibitor for the treatment of CML.

scholarly journals Identification of a novel common proviral integration site, flit-1, in feline leukemia virus induced thymic lymphoma

Virology ◽  
2009 ◽  
Vol 386 (1) ◽  
pp. 16-22 ◽  
Author(s):  
Yasuhito Fujino ◽  
Chun-Peng Liao ◽  
Yan Shi Zhao ◽  
Judong Pan ◽  
Lawrence E. Mathes ◽  
...  
Keyword(s):  
Integration Site ◽  
Leukemia Virus ◽  
Feline Leukemia Virus ◽  
Proviral Integration ◽  
Thymic Lymphoma ◽  
Proviral Integration Site

scholarly journals Proviral Integration Site for Moloney Murine Leukemia Virus (PIM) Kinases Promote Human T Helper 1 Cell Differentiation

2012 ◽  
Vol 288 (5) ◽  
pp. 3048-3058 ◽  
Author(s):  
Johanna Tahvanainen ◽  
Minna K. Kyläniemi ◽  
Kartiek Kanduri ◽  
Bhawna Gupta ◽  
Hanna Lähteenmäki ◽  
...  
Keyword(s):  
Murine Leukemia Virus ◽  
Integration Site ◽  
Leukemia Virus ◽  
Moloney Murine Leukemia Virus ◽  
T Helper ◽  
T Helper 1 ◽  
Proviral Integration ◽  
Proviral Integration Site ◽  
Pim Kinases ◽  
Murine Leukemia

scholarly journals Relationship between the transcriptional expression of PIM1 and local control in patients with head and neck squamous cell carcinomas treated with radiotherapy

2022 ◽  
Author(s):  
Xavier León ◽  
Jacinto García ◽  
Albert Pujol ◽  
Julia de Juan ◽  
Rosselin Vásquez ◽  
...  
Keyword(s):  
Local Recurrence ◽  
Head And Neck ◽  
Local Control ◽  
Squamous Cell ◽  
Integration Site ◽  
Leukemia Virus ◽  
Transcriptional Expression ◽  
Proviral Integration Site ◽  
Increased Risk ◽  
Elevated Expression

Abstract Purpose Proviral integration site for Moloney murine leukemia virus (PIMs) are proto-oncogenes encoding serine/threonine kinases that phosphorylate a variety of substrates involved in the regulation of cellular processes. Elevated expression of PIM-1 has been associated with poor prognosis in several types of cancer. There are no studies that have analyzed the response to radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) according to the expression of PIM-1. The aim of our study was to analyze the relationship between the transcriptional expression of PIM-1 and local response to radiotherapy in HNSCC patients. Methods We determined the transcriptional expression of PIM-1 in 135 HNSCC patients treated with radiotherapy, including patients treated with chemoradiotherapy (n = 65) and bioradiotherapy (n = 15). Results During the follow-up, 48 patients (35.6%) had a local recurrence of the tumor. Patients with local recurrence had a higher level of PIM-1 expression than those who achieved local control of the disease (P = 0.017). Five-year local recurrence-free survival for patients with a high expression of PIM-1 (n = 43) was 44.6% (95% CI 29.2–60.0%), and for patients with low expression (n = 92) it was 71.9% (95% CI 62.5–81.3%) (P = 0.007). According to the results of multivariate analysis, patients with a high PIM-1 expression had a 2.2-fold increased risk of local recurrence (95% CI 1.22–4.10, P = 0.009). Conclusion Patients with elevated transcriptional expression levels of PIM-1 had a significantly higher risk of local recurrence after radiotherapy.

Understanding PIM-1 kinase inhibitor interactions with free energy simulation

2019 ◽  
Vol 21 (14) ◽  
pp. 7544-7558 ◽  
Author(s):  
Xiaohui Wang ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Kinase Inhibitor ◽  
Integration Site ◽  
Leukemia Virus ◽  
Energy Simulation ◽  
Proviral Integration ◽  
Proviral Integration Site ◽  
Moloney Leukemia Virus

The proviral integration site of the Moloney leukemia virus (PIM) family includes three homologous members.

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