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Objective and design: This observational study investigated the regulatory mechanism of Pim-1 in inflammatory signaling pathways. Materials: THP-1, RAW 264.7, BV2, and Jurkat human T cell lines were used. Treatment: None. Methods: Lipopolysaccharide (LPS) was used to induce inflammation, followed by PIM1 knockdown. Western blot, immunoprecipitation, immunofluorescence, and RT-PCR assays were used to assess the effect of PIM1 knockdown on LPS-induced inflammation. Results: PIM1 knockdown in macrophage-like THP-1 cells suppressed LPS-induced upregulation of pro-inflammatory cytokines, inducible nitric oxide synthase, cyclooxygenase-2, phosphorylated Janus kinase, signal transducer and activator of transcription 3, extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, and nuclear factor kappa B p65 (NF-κB p65). It also suppressed upregulation of inhibitor of NF-κB kinase α/β and enhanced the nuclear translocation of NF-κB p65. Moreover, it inhibited the upregulation of Nod-like receptor family pyrin domain-containing 3 (NLRP3) and cleavage of caspase-1 induced by co-treatment of LPS with adenosine triphosphate. Additionally, p-transforming growth factor-β-activated kinase 1 (TAK1) interacted with Pim-1. All three members of Pim kinases (Pim-1, Pim-2, and Pim-3) were required for LPS-mediated inflammation in macrophages; however, unlike Pim-1 and Pim-3, Pim-2 functioned as a negative regulator of T cell activity. Conclusions: Pim-1 interacts with TAK1 in LPS-induced inflammatory responses and is involved in MAPK/NF-κB/NLRP3 signaling pathways. Additionally, considering the negative regulatory role of Pim-2 in T cells, further in-depth studies on their respective functions are needed. [ABSTRACT FROM AUTHOR]

PIM-1 kinase is a serine-threonine phosphorylating enzyme with implications in multiple types of malignancies, including prostate, breast, and blood cancers. Developing better search methodologies for PIM-1 kinase inhibitors may be a good strategy to speed up the discovery of an oncological drug approved for targeting this specific kinase. Computer-aided screening methods are promising approaches for the discovery of novel therapeutics, although certain limitations should be addressed. A frequent omission that is encountered in molecular docking is the lack of proper implementation of scoring functions and algorithms on the post-docking results, which usually alters the outcome of the virtual screening. The current study suggests a method for post-processing docking results, expressed either as binding affinity or score, that considers different binding modes of known inhibitors to the studied targets while making use of in vitro data, where available. The docking protocol successfully discriminated between known PIM-1 kinase inhibitors and decoy molecules, although binding energies alone were not sufficient to ensure a successful prediction. Logistic regression models were trained to predict the probability of PIM-1 kinase inhibitory activity based on binding energies and the presence of interactions with identified key amino acid residues. The selected model showed 80.9% true positive and 81.4% true negative rates. The discussed approach can be further applied in large-scale molecular docking campaigns to increase hit discovery success rates. [ABSTRACT FROM AUTHOR]

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]

In the current medical era, developing new PIM-1 inhibitors stands as a significant approach to cancer management due to the pivotal role of PIM-1 kinase in promoting cell survival, proliferation, and drug resistance in various cancers. This study involved designing and synthesizing new derivatives of pyrazolo[1,5-a]pyrimidines (6a-i) and pyrazolo[3,4-b]pyridines (10a-i) as potential anti-cancer agents targeting PIM-1 kinase. The cytotoxicity was screened on three cancer cell lines: A-549 (lung), PANC-1 (pancreatic), and A-431 (skin), alongside MRC5 normal lung cells to assess selectivity. Several pyrazolo[1,5-a]pyrimidines (6b, 6c, 6g, 6h, and 6i) and pyrazolo[3,4-b]pyridine (10f) demonstrated notable anticancer properties, particularly against A-549 lung cancer cells (IC 50 range: 1.28-3.52 μM), also they exhibited significantly lower toxicity towards MRC5 normal cells. Thereafter, the compounds were evaluated for their inhibitory activity against PIM-1 kinase. Notably, 10f, bearing a 4-methoxyphenyl moiety, demonstrated good inhibition of PIM-1 with an IC 50 of 0.18 μM. Additionally, 10f induced apoptosis and arrested cell cycle progression in A-549 cells. Molecular docking and dynamics simulations provided insights into the binding interactions and compounds' stability with PIM-1 kinase. The results highlight these compounds, especially 10f, as promising selective anticancer agents targeting PIM-1 kinase., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

PIM-1 kinase is a serine-threonine phosphorylating enzyme with implications in multiple types of malignancies, including prostate, breast, and blood cancers. Developing better search methodologies for PIM-1 kinase inhibitors may be a good strategy to speed up the discovery of an oncological drug approved for targeting this specific kinase. Computer-aided screening methods are promising approaches for the discovery of novel therapeutics, although certain limitations should be addressed. A frequent omission that is encountered in molecular docking is the lack of proper implementation of scoring functions and algorithms on the post-docking results, which usually alters the outcome of the virtual screening. The current study suggests a method for post-processing docking results, expressed either as binding affinity or score, that considers different binding modes of known inhibitors to the studied targets while making use of in vitro data, where available. The docking protocol successfully discriminated between known PIM-1 kinase inhibitors and decoy molecules, although binding energies alone were not sufficient to ensure a successful prediction. Logistic regression models were trained to predict the probability of PIM-1 kinase inhibitory activity based on binding energies and the presence of interactions with identified key amino acid residues. The selected model showed 80.9% true positive and 81.4% true negative rates. The discussed approach can be further applied in large-scale molecular docking campaigns to increase hit discovery success rates.

Recently, we have developed novel Pim-1 kinase inhibitors starting from a dihydrobenzofuran core structure using a computational approach. Here, we report the design and synthesis of stilbene-based Pim-1 kinase inhibitors obtained by formal elimination of the dihydrofuran ring. These inhibitors of the first design cycle, which were obtained as inseparable cis/trans mixtures, showed affinities in the low single-digit micromolar range. To be able to further optimize these compounds in a structure-based fashion, we determined the X-ray structures of the protein-ligand-complexes. Surprisingly, only the cis-isomer binds upon crystallization of the cis/trans-mixture of the ligands with Pim-1 kinase and the substrate PIMTIDE, the binding mode being largely consistent with that predicted by docking. After crystallization of the exclusively trans-configured derivatives, a markedly different binding mode for the inhibitor and a concomitant rearrangement of the glycine-rich loop is observed, resulting in the ligand being deeply buried in the binding pocket., (© 2024 The Authors. Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Cancer is an unimpeded growth of cells leading to metathesis of cancer and eventually spread throughout the body. PIM kinases are the members of the serine threonine kinase playing role in cancer progression, differentiation and proliferation. Till date there is no single drug targeting PIM-1 kinase in the market, that has made itself a target in limelight for the discover of new anticancer agents. The contemporary research focusses on the development of new inhibitors of PIM-1 kinase by application of ligand-based and structure-based perspective of drug discovery namely 3D-QSAR, molecular docking and dynamics. The following study stated the correlation amid structural and biological activity of the compounds employing 3D-QSAR analysis. Three 3D-QSAR models were generated using 33 molecules from which the excellent model stated an encouraging conventional correlation coefficient ( r 2 ) 0.8651 , cross validation coefficient (q 2 ) 0.7609 . Furthermore, the predicted correlation coefficient (r 2 pred ) 0.6274, resided in the active pocket of PIM-1 kinase establishing hydrogen bond interactions with Asp186 in the DFG motif; similarly, all other molecules were engaged within the active site of the PIM-1 kinase. Moreover, molecular dynamics simulation study stated the stability of the ligand in the active site of PIM-1 kinase protein by developing two hydrogen bonds throughout the trajectory of 100 ns. In nutshell, the output stated the successful application of ligand and structure-based strategy for the development of novel PIM-1 kinase inhibitors as anticancer agents.Communicated by Ramaswamy H. Sarma.26 resided in the active pocket of PIM-1 kinase establishing hydrogen bond interactions with Asp186 in the DFG motif; similarly, all other molecules were engaged within the active site of the PIM-1 kinase. Moreover, molecular dynamics simulation study stated the stability of the ligand in the active site of PIM-1 kinase protein by developing two hydrogen bonds throughout the trajectory of 100 ns. In nutshell, the output stated the successful application of ligand and structure-based strategy for the development of novel PIM-1 kinase inhibitors as anticancer agents.Communicated by Ramaswamy H. Sarma.

[Display omitted] • A new series of 3-cyanopyridines were synthesized as PIM-1 kinase inhibitors. • Anti-tumor activity was assessed against PC-3 and DU-145 prostate cancer cell lines. • Compounds 2b , 3b , 4b , and 5b revealed high potency and high safety profiles. • Nanoparticles formulation of compound 3b was prepared that improved the activity. • Molecular docking and dynamic simulation was done in the PIM-1 active site. Recently, inhibition of PIM-1 enzyme is found as an effective route in the fight against proliferation of cancer. Herein, new cyano pyridines that target PIM-1 kinase were designed, synthesized, and biologically evaluated. Two prostate cell lines were used to examine each of the new compounds in vitro for anticancer activity, namely, PC-3 and DU-145. The cyanopyridine derivatives 2b , 3b , 4b , and 5b with an N,N-dimethyl phenyl group at the pyridine ring's 4-position showed considerable antitumor effect on the tested cell lines. Additionally, the high selectivity index revealed that these compounds were less cytotoxic to normal WI-38 cells. Furthermore, they exhibited strong inhibitory effect on PIM-1 having IC 50 = 0.248, 0.13, 0.326 and 0.245 μM, respectively. The most powerful derivatives 2b , 3b , 4b , and 5b , were chosen for further examination of their inhibitory potential on both kinases (PIM-2 and PIM-3). Interestingly, upon loading compound 3b in a cubosomes formulation with nanometric size, improvements in cytotoxicity and inhibitory effect on PIM-1 kinase were observed. In silico ADME parameters study revealed that compound 3b is orally bioavailable without penetration to the blood-brain barrier. Further, the docking simulations revealed the ability of our potent compounds to well accommodate the PIM-1 kinase active site forming stable complexes. In a 150 ns MD simulation, the most powerful PIM-1 inhibitor 3b produced stable complex with the PIM-1 enzyme (RMSD = 1.76). Furthermore, the 3b –PIM-1 complex has the low binding free energy (−242.2 kJ/mol) according to the MM-PBSA calculations. [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]

Background: PIM (Proviral Integration site for Moloney Murine Leukemia virus) kinases are members of the class of kinase family serine/ threonine kinases, which play a crucial role in cancer development. As there is no drug in the market against PIM-1, kinase has transpired as a budding and captivating target for discovering new anticancer agents targeting PIM-1 kinase., Aim: The current research pondered the development of new PIM-1 kinase inhibitors by applying a ligand-based and structure-based drug discovery approach involving 3D QSAR, molecular docking, and dynamics simulation., Method: In this study, association allying the structural properties and biological activity was undertaken using 3D-QSAR analysis. The 3D-QSAR model was generated with the help of 35 compounds from which the best model manifested an appreciated cross-validation coefficient (q2) of 0.8866 and conventional correlation coefficient (r2) of 0.9298, respectively and predicted correlation coefficient (r2 pred) was obtained as 0.7878., Result: The molecular docking analysis demonstrated that the analogs under analysis occupied the active site of PIM-1 kinase receptor and interactions with Lys67 in the catalytic region, Asp186 in the DFG motif, and Glu171 were noticed with numerous compounds., Discussion: Furthermore, the molecular dynamics simulation study stated that the ligand portrayed the strong conformational stability within the active site of PIM-1 kinase protein, forming of two hydrogen bonds until 100 ns, respectively., Conclusion: Overall outcomes of the study revealed that applications of the ligand-based drug discovery approach and structure-based drug discovery strategy conceivably applied to discovering new PIM-1 kinase inhibitors as anticancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)