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PIM-1 kinase belongs to the Ser/Thr kinases family, an attractive therapeutic target for prostate cancer. Here, we screened about 100 natural substances to find potential PIM-1 inhibitors. Two natural compounds, Naringenin and Quercetin, were finally selected based on their PIM-1 inhibitory potential and binding affinities. The docking score of Naringenin and Quercetin with PIM-1 is −8.4 and − 8.1 kcal/mol, respectively. Fluorescence binding studies revealed a strong affinity (K a values, 3.1 × 104 M−1 and 4.6 × 107 M−1 for Naringenin and Quercetin, respectively) with excellent IC 50 values for Naringenin and Quercetin (28.6 μM and 34.9 μM, respectively). Both compounds inhibited the growth of prostate cancer cells (LNCaP) in a dose-dependent manner, with the IC 50 value of Naringenin at 17.5 μM and Quercetin at 8.88 μM. To obtain deeper insights into the PIM-1 inhibitory effect of Naringenin and Quercetin, we performed extensive molecular dynamics simulation studies, which provided insights into the binding mechanisms of PIM-1 inhibitors. Finally, Naringenin and Quercetin were suggested to serve as potent PIM-1 inhibitors, offering targeted treatments of prostate cancer. In addition, our findings may help to design novel Naringenin and Quercetin derivatives that could be effective in therapeutic targeting of prostate cancer. • PIM-1 is an attractive drug target for prostate cancer therapy. • We have discovered Naringenin and Quercetin as potent PIM-1 kinase inhibitors. • Docking and MD simulation studies suggested a strong binding and the formation of stable protein-ligands complexes. • Naringenin and Quercetin significantly inhibit the activity of PIM-1 with excellent IC50 values. • Both compounds show cytotoxic effect on LNCaP cells with admirable IC 50 values. [ABSTRACT FROM AUTHOR]

A series of novel thiazolidine-2,4-dione derivatives 4a-x have been designed, synthesized and evaluated for potential anti-cancer activity. The anti-cancer activity of synthesized compounds 4a-x were evaluated against selected human cancer cell line of breast (MCF-7) using sulforhodamine B (SRB) method. Among the synthesized compounds, 4x having 2-cyano phenyl group showed significant cytotoxic activity which is comparable to that of adriamycin as standard anti-cancer drug. The SAR study revealed that the substituted phenyl group on oxadiazole ring attached to thiazolidine-2,4-dione moiety showed significant growth inhibitory activity against MCF-7 cell line. The result of molecular modeling studies showed that compounds 4f , 4o and 4x having similar structural alignment as crystal ligand of protein (PDB code: 4DTK ) and exhibited hydrogen bond interaction with amino acid residues LYS67, GLU171, ASP128 and ASP186 of PIM-1 kinase. The results of biological activity and docking study revealed that the presence of electron withdrawing group at 2 position of phenyl ring attached to oxadiazole of thiazolidine-2,4-dione scaffold is crucial for better anti-cancer activity. [ABSTRACT FROM AUTHOR]

Targeting Pim-1 kinase recently proved to be profitable for conquering cancer proliferation. In the current study, we report the design, synthesis and biological evaluation of two novel series of 2-amino cyanopyridine series ( 5a-g ) and 2-oxocyanopyridine series ( 6a-g ) targeting Pim-1 kinase. All of the newly synthesized compounds were evaluated for their in vitro anticancer activity against a panel of three cell lines, namely, the liver cancer cell line (HepG2), the colon cancer cell line (HCT-116) and the breast cancer cell line (MCF-7). Most of the compounds showed good to moderate anti-proliferative activity against HepG2 and HCT-116 cell lines while only few compounds showed significant cytotoxic activity against MCF-7 cell line. Further, the Pim-1 kinase inhibitory activity for the two series was evaluated where most of the tested compounds showed marked Pim-1 kinase inhibitory activity (26%–89%). Moreover, determination of the IC 50 values unraveled very potent molecules in the submicromolar range where compound 6c possessed an IC 50 value of 0.94 μM . Moreover, apoptosis studies were conducted on the most potent compound 6c to evaluate the proapoptotic potential of our compounds. Interestingly, it induced the level of active caspase 3 and boosted the Bax/Bcl2 ratio 22704 folds in comparison to the control. Finally, a molecular docking study was conducted to reveal the probable interaction with the Pim-1 kinase active site. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is a growing epidemic, and as a consequence the number of obese pregnancies has also increased. Pregnancy is characterised by maternal and placental inflammation which is intensified with maternal obesity. The proviral integration site for Moloney murine leukemic virus (Pim)-1 protein is a serine/threonine kinase involved in a wide range of inflammatory diseases. In relation to obesity, however, its role has not been elucidated in human placenta. The aims were to determine the placental expression of Pim-1 with pre-existing maternal obesity and its role in regulating placental inflammation associated with obesity.Methods: Human placenta was obtained at the time of term Caesarean section from lean and pre-existing obese pregnant women to determine the effect of maternal obesity on Pim-1 expression. To determine the effect of Pim-1 on the inflammatory response induced by bacterial endotoxin LPS and pro-inflammatory cytokines TNF-α or IL-1β, the chemical inhibitor SMI-4a and siRNA were used.Results: Pim-1 protein and mRNA expression was significantly increased in placenta of obese women. SMI-4a significantly suppressed the expression and release of pro-inflammatory cytokine IL-6 and chemokines GRO-α and MCP-1 when stimulated with LPS or TNF-α in placenta. Primary trophoblast cells transfected with Pim-1 siRNA had decreased expression and release of pro-inflammatory cytokines IL-1β, IL-6, chemokines GRO-α and MCP-1, when stimulated with LPS, TNF-α or IL-1β.Discussion: The findings from this study implicate Pim-1 may contribute to placental inflammation in pregnancies complicated by maternal obesity. Thus, therapeutic targets for Pim-1 may improve fetal outcomes complicated by obese pregnancies. [ABSTRACT FROM AUTHOR]

The proviral insertion site in moloney murine leukemia virus (PIM) is a family of serine/threonine kinase of Ca 2+ -calmodulin-dependent protein kinase (CAMK) group which is responsible for the activation and regulation of cellular transcription and translation. The three isoforms of PIM kinase (PIM-1, PIM-2 and PIM-3) share high homology and functional idleness are widely expressed and involved in a variety of biological processes including cell survival, proliferation, differentiation and apoptosis. Altered expression of PIM-1 kinase correlated with hematologic malignancies and solid tumors. In the present study, atom-based 3D-QSAR, docking and virtual screening studies have been performed on a series of thiazolidine-2,4-dione derivatives as PIM-1 kinase inhibitors. 3D-QSAR and docking approach has shortlisted the most active thiazolidine-2,4-dione derivatives such as 28, 31, 33 and 35 with the incorporation of more than one structural feature in a single molecule. External validations by various parameters and molecular docking studies at the active site of PIM-1 kinase have proved the reliability of the developed 3D-QSAR model. The generated pharmacophore (AADHR.33) from 3D-QSAR study was used for screening of drug like compounds from ZINC database, where ZINC15056464 and ZINC83292944 showed potential binding affinities at the active site amino acid residues (LYS67, GLU171, ASP128 and ASP186) of PIM-1 kinase (PDB ID: 4DTK ). The results of this study may be useful for (medicinal) chemists to design more potent thiazolidine-2,4-dione analogs as PIM-1 kinase inhibitors. [ABSTRACT FROM AUTHOR]

As one of the most malignant breast cancer types, triple-negative breast cancer (TNBC) treatment is a particularly great challenge in the current era of precision medicine. Due to the limited effectiveness and targeting of current treatment methods, it is urgently need to develop an effective precision strategy to combat TNBC. Herein, a novel TNBC targeted molecular drug based on zinc(II) phthalocyanine (BF-Pc) was rationally designed by conjugating a Pim-1 kinase inhibitor with high TNBC selectivity. In our in vitro investigation, BF-Pc not only exhibits extremely high targeting to TNBC cells overexpressed Pim-1 kinases, but also shows ultra-efficient photocytotoxicity toward TNBC cells far beyond the normal cells. Significantly, BF-Pc -induced PDT can obviously suppress TNBC cell migration and invasion. The proposed manner in our work offers a promising approach to combat TNBC effectively and precisely. [Display omitted] • A novel targeted photosensitizers designed to combat triple negative breast cancer. • BF-Pc exhibits high affinity to triple negative breast cancer cells. • BF-Pc has remarkable photocytotoxicity and reduced toxicity toward normal cells. • BF-Pc can significantly inhibit the migration of triple negative breast cancer cells. [ABSTRACT FROM AUTHOR]

[Display omitted] Pim-1 kinase is a serine/threonine kinase which is vital in many tumors. The Pim-1 inhibitor 10-DEBC and its derivatives discovered in our previous work were modified through macrocyclization strategy. A series of benzo[ b ]pyridine[4,3-e][1,4]oxazine macrocyclic compounds were designed, synthesized, and evaluated as novel Pim-1 kinase inhibitors. Among these compounds, compound H5 exhibited the highest activity with an IC 50 value of 35 nM. In addition, the crystal complex structure of Pim-1 kinase bound with compound H3 was determined, and the structure–activity relationship of these macrocyclic compounds was analyzed, which provides the structural basis of further optimization of novel macrocyclic Pim-1 kinase inhibitors.. [ABSTRACT FROM AUTHOR]

Abstract: Overexpression of the ATP-binding cassette (ABC) drug efflux proteins P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on malignant cells is associated with inferior chemotherapy outcomes. Both, ABCB1 and ABCG2, are substrates of the serine/threonine kinase Pim-1; Pim-1 knockdown decreases their cell surface expression, but SGI-1776, the first clinically tested Pim inhibitor, was shown to reverse drug resistance by directly inhibiting ABCB1-mediated transport. We sought to characterize Pim-1-dependent and -independent effects of SGI-1776 on drug resistance. SGI-1776 at the Pim-1-inhibitory and non-cytotoxic concentration of 1μM decreased the IC50s of the ABCG2 and ABCB1 substrate drugs in cytotoxicity assays in resistant cells, with no effect on the IC50 of non-substrate drug, nor in parental cells. SGI-1776 also increased apoptosis of cells overexpressing ABCG2 or ABCB1 exposed to substrate chemotherapy drugs and decreased their colony formation in the presence of substrate, but not non-substrate, drugs, with no effect on parental cells. SGI-1776 decreased ABCB1 and ABCG2 surface expression on K562/ABCB1 and K562/ABCG2 cells, respectively, with Pim-1 overexpression, but not HL60/VCR and 8226/MR20 cells, with lower-level Pim-1 expression. Finally, SGI-1776 inhibited uptake of ABCG2 and ABCB1 substrates in a concentration-dependent manner irrespective of Pim-1 expression, inhibited ABCB1 and ABCG2 photoaffinity labeling with the transport substrate [125I]iodoarylazidoprazosin ([125I]IAAP) and stimulated ABCB1 and ABCG2 ATPase activity. Thus SGI-1776 decreases cell surface expression of ABCB1 and ABCG2 and inhibits drug transport by Pim-1-dependent and -independent mechanisms, respectively. Decrease in ABCB1 and ABCG2 cell surface expression mediated by Pim-1 inhibition represents a novel mechanism of chemosensitization. [Copyright &y& Elsevier]

Objectives: The goal of this study was to demonstrate the enhancement of human cardiac progenitor cell (hCPC) reparative and regenerative potential by genetic modification for the treatment of myocardial infarction. Background: Regenerative potential of stem cells to repair acute infarction is limited. Improved hCPC survival, proliferation, and differentiation into functional myocardium will increase efficacy and advance translational implementation of cardiac regeneration. Methods: hCPCs isolated from the myocardium of heart failure patients undergoing left ventricular assist device implantation were engineered to express green fluorescent protein (hCPCe) or Pim-1-GFP (hCPCeP). Functional tests of hCPC regenerative potential were performed with immunocompromised mice by using intramyocardial adoptive transfer injection after infarction. Myocardial structure and function were monitored by echocardiographic and hemodynamic assessment for 20 weeks after delivery. hCPCe and hCPCeP expressing luciferase were observed by using bioluminescence imaging to noninvasively track persistence. Results: hCPCeP exhibited augmentation of reparative potential relative to hCPCe control cells, as shown by significantly increased proliferation coupled with amelioration of infarction injury and increased hemodynamic performance at 20 weeks post-transplantation. Concurrent with enhanced cardiac structure and function, hCPCeP demonstrated increased cellular engraftment and differentiation with improved vasculature and reduced infarct size. Enhanced persistence of hCPCeP versus hCPCe was revealed by bioluminescence imaging at up to 8 weeks post-delivery. Conclusions: Genetic engineering of hCPCs with Pim-1 enhanced repair of damaged myocardium. Ex vivo gene delivery to modify stem cells has emerged as a viable option addressing current limitations in the field. This study demonstrates that efficacy of hCPCs from the failing myocardium can be safely and significantly enhanced through expression of Pim-1 kinase, setting the stage for use of engineered cells in pre-clinical settings. [Copyright &y& Elsevier]

Abstract: Pim-1 kinase is a cytoplasmic serine/threonine kinase that controls programmed cell death by phosphorylating substrates that regulate both apotosis and cellular metabolism. A series of 2-styrylquinolines and quinoline-2-carboxamides has been identified as potent inhibitors of the Pim-1 kinase. The 8-hydroxy-quinoline 7-carboxylic acid moiety appeared to be a crucial pharmacophore for activity. Molecular modeling indicated that interaction of this scaffold with Asp186 and Lys67 residues within the ATP-binding pocket might be responsible for the kinase inhibitory potency. [Copyright &y& Elsevier]

Abstract: A series of substituted 3-aryl-6-amino-triazolo[4,3-b]pyridazines were identified as highly selective inhibitors of Pim-1 kinase. Initial exploration identified compound 24 as a potent, selective inhibitor, limited in its utility by poor solubility and permeability. Understanding the unusual ATP-binding site of the Pim kinases and X-ray crystallographic data on compound 24 led to design improvements in this class of inhibitor. This resulted in compound 29, a selective, soluble and permeable inhibitor of Pim-1. [Copyright &y& Elsevier]

Abstract: A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC50 =50nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R1 phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor. [Copyright &y& Elsevier]

Abstract: The proto-oncogene Pim-1 encodes a serine-threonine kinase which is a downstream effector of cytokine signaling and can enhance cell cycle progression by altering the activity of several cell cycle regulators among them the G1 specific inhibitor p21Waf, the phosphatase Cdc25A and the kinase C-TAK1. Here, we demonstrate by using biochemical assays that Pim-1 can interact with the phosphatase Cdc25C and is able to directly phosphorylate the N-terminal region of the protein. Cdc25C is functionally related to Cdc25A but acts specifically at the G2/M cell cycle transition point and can be inactivated by C-TAK1-mediated phosphorylation. Immuno-fluorescence experiments showed that Pim-1 and Cdc25C co-localize in the cytoplasm of both epithelial and myeloid cells. We find that phosphorylation by Pim-1 enhances the phosphatase activity of Cdc25C and in transfected cells that are arrested in G2/M by bleomycin, Pim-1 can enhance progression into G1. Therefore, we propose that Pim-1 activates Cdc25C by a direct phosphorylation and can thereby assume the function of a positive cell cycle regulator at the G2/M transition. [Copyright &y& Elsevier]

• Novel pyrazolo[3,4- b ]pyridine scaffold-based derivatives were synthesized and characterized. • Both Compound 17 and 19 were found to be potent and selective against MCF-7 cells through apoptosis-inducing activity. • Both compounds 17 and 19 were good inhibitors for PIM-1 kinase in both enzymatic, RT-PCR, and in silico assays. Pim-1 kinase targeted recently has proved an essential goal of breast cancer therapy. We report the design, synthesis with full characterization analysis of pyrazolo[3,4- b ]pyridine scaffold-based derivatives targeting Pim-1 kinase as anti-breast cancer agents. All the newly synthesized compounds were screened for their in vitro cytotoxic activity against two breast cancer cell lines MCF-7 and MDA-MB-231, and non-cancerous MCF-10A cells. Four derivatives notably, 17 and 19 exhibited a remarkable cytotoxic activity with IC 50 values 5.98 and 5.61 µM against MCF-7 (ERα-dependent) cells in a selective way, as they weren't active against MDA-MB-231 (non-ERα-dependent) and safe against MCF-10A. The most active compounds through in vitro screening were subjected to PIM-1 kinase to elucidate the Pim-1 kinase inhibitory activity as the mechanistic mode of action. Among the tested derivatives, Compounds 17 and 19 showed the highest inhibitory activity with IC 50 values 43 and 26 nM, respectively, compared to the 5-FU with IC 50 value 17 nM. Moreover, apoptotic investigation through flow cytometry and gene expression analysis of the apoptosis-related genes for the most active compound 19 against MCF-7. It was found that compound 19 induced apoptotic MCF-7 cell death by cell cycle arrest at G2/M phase and by elevation the expression of pro-apoptotic genes and inhibition of anti-apoptotic genes expression. Finally, the PIM-1 inhibition activities for compounds 17 and 19 were in accordance with the molecular docking study that revealed good interaction with the Pim-1 kinase active site. [ABSTRACT FROM AUTHOR]

The PIM kinases are a family of serine/threonine kinase belongs to the Ca2+/calmodulin-dependent protein kinase (CAMK) group. Aberrations of PIM kinase pathway may be associated with the development of various types of cancer. In the present manuscript, pharmacophore modeling, 3D-QSAR and docking studies have been performed on pyrazolo-pyrimidine derivatives to identify the essential features required for the development of potential inhibitors. The phase developed pharmacophore hypothesis (ADRR_1) consist of the essential features such as, one hydrogen bond acceptor, one hydrogen bond donor, and two aromatic rings, required for the activity. The 3D-QSAR studies were performed by the using atom-based and field-based methods which generate high regression coefficients for the training (r2 = 0.87; 0.96) and test (Q2 = 0.71; 0.69) sets, consecutively. The docking study showed good binding interactions with essential amino acids such as LYS67, GLU12, ASP128 and GLU171. The virtual screening studies have been performed through ZINC database by using pharmacophore ADRR_1, which produced 7006 drug like molecules. These molecules further proceed through different docking methodologies and screened four hit compounds namely, ZINC12941871, ZINC59456449, ZINC59456489, and ZINC59456444. The compound ZINC59456449 showed best docked pose (similar to crystal ligand) with docking scores, XP (−8.42 kcal/mol) and SP (−7.94 kcal/mol). The ADME and MMGBSA parameters showed the excellent value which may be used for the optimization of potent compounds. These results may further help to the scientists for the development of novel compounds against PIM-1 kinase. The phase developed pharmacophore hypothesis (ADRR_1) with structure activity relationships (SARs) of pyrazolo-pyrimidine scaffold with different possible substituent's on the basis of results obtained by 3D-QSAR study. Image 1 • 3D-QSAR and docking studies pyrazolo-pyrimidine derivatives. • Pharmacophore hypothesis (ADRR_1) consists of the essential features. • The virtual screening studies have been performed through ZINC database. • The ADME and MMGBSA parameters showed the excellent value. [ABSTRACT FROM AUTHOR]