A strong correlation was observed between our MD simulation, spectroscopic, and enzymatic activity studies. Understanding the pH-dependent structural changes of PIM-1 can provide insights into its role in disease conditions and cellular homeostasis, particularly regarding protein function under varying pH conditions.

Several of these substances are now being studied in clinical trials due to their promising outcomes. This article provides a thorough examination of the PIM1 kinase pathways and the recent advancements in producing PIM1 kinase inhibitors for the treatment of cancer.

Compound 3 exhibited an IC50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC50 of 0.06 µM. However, compound 3 demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound 3 is a promising anticancer agent with the potential for further development into a highly active compound.

Interestingly, most of the identified amino acids correspond to cancer-associated amino acid changes, validating our results. In total, this work provides insights not only on the details of SRPK1 inhibition by the PIM-1L SR/SH-domain, but also contributes to an in-depth understanding of SRPK1 regulation.

The observed inhibitory effects of PIM1 can inhibit tumor growth, induce cell cycle arrest, and promote apoptosis. However, further in vitro and in vivo studies are needed to confirm their anticancer potentials and elucidate the underlying molecular mechanisms of these compounds in GBM treatment.

These findings provide insights into the structural interactions between flavonoids and Pim-1 kinase, offering a foundation for future experimental investigations. However, further studies, including in vitro and in vivo validation, are necessary to assess the pharmacological relevance and specificity of flavonoids in cancer therapy.

Two compounds, namely, radotinib and capmatinib, were identified as top compounds using molecular docking. The Western blot analysis assay showed that the phosphorylation level of STAT3 was significantly decreased upon radotinib treatment. Taken together, our findings suggest that radotinib, which is currently used in the treatment of chronic myeloid leukemia (CML), could be considered as a potential candidate for repurposing in the treatment of HCC.

Based on the results, four new inhibitors were designed, demonstrating better inhibition efficiency with the PIM1 kinase compared to the reference compounds. Moreover, the designed compounds underwent evaluation for ADMET, yielding promising results.

Based on these studies, we suggest PIM1 as a potential therapeutic target for immunoinflammatory diseases and a valid candidate for future research. Herein, for the first time, we provide a detailed review that focuses on the roles of PIM1 in the pathogenesis of immunoinflammatory diseases.

Later, analysis of 4g showed good drug-ability and pharmacokinetic properties. A similar mode of interaction at the ATP-binding site of c-Met and Pim-1 compared to the docked ligands was suggested by additional docking studies of compound 4g.

A few small chemical inhibitors (E.g., SGI-1776, AZD1208, LGH447) that specifically target the PIM proteins' adenosine triphosphate (ATP)-binding domain have been identified. We explore the involvement of oncogenic transcription factor c-Mycandmi-RNA in relation to PIM kinase. In this article, we highlight the oncogenic effects, and structural insights into PIM kinase inhibitors for the treatment of cancer.

PIM1/GSK3β signaling is activated in clinical samples of osimertinib-resistant NSCLC, and dual epidermal growth factor receptor (EGFR)/PIM1 blockade synergistically reverse osimertinib-resistant NSCLC in vivo. These data identify PIM1 as a driver of EMT-associated osimertinib-resistant NSCLC cells and predict that PIM1 inhibitors and osimertinib combination therapy will provide clinical benefit in patients with EGFR-mutant NSCLC.

Csn-B combined with imatinib can enhance ROS expression and induce apoptosis of K562 cells through Nur77/Pim-1/Drp1 pathway.

Among these, compound 52 exhibited the best binding affinity, with a docking score of -13.03 kcal/mol. Finally, molecular dynamics (MD) studies were conducted to confirm the stability of the protein-ligand complexes obtained from docking the studied compounds to PIM-1 kinase, validating the potential of these compounds as PIM-1 kinase inhibitors.

Additionally, we discovered that elevated Pim-1 expression is dependent on the trimethylation of histone H3 lysine 9 during liver IR. These findings underscore the importance and potential clinical application of targeting Pim-1 in treating hepatic IR, presenting a novel therapeutic avenue.

Specifically, we demonstrate that JAK/STAT pathway mutations induce the overexpression of the PIM1 gene. Moreover, we show that the pan-PIM inhibitor, PIM447, significantly reduces the leukemogenesis, as well as the aberrant activation of c-MYC and mTOR pathways in cells expressing different JAK/STAT pathway mutations, becoming a potential therapeutic opportunity for a relevant subset of T-ALL/LBL patients.

Interestingly, PIM1 interacts with histone deacetylase 2 (HDAC2) and downregulates its level via phosphorylation, thereby altering the epigenetic profiles of Wnt signaling pathway genes. Collectively, these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis, which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.

Finally, Naringenin and Quercetin may serve as potent PIM-1 inhibitors, offering intriguing prospects for the advancement of PIM-1-targeted anti-cancer treatments for 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.

Furthermore, Dual blockade of Pim1 and PD-1 collaboratively suppressed tumor growth, repolarized macrophages, and boosted the efficacy of anti-PD-1 antibody. Collectively, our findings elucidate the pivotal role of PIM1 in orchestrating TAMs within the TME of NSCLC and highlight the potential of PIM1 inhibition as a strategy for enhancing the efficacy of cancer immunotherapy.

We demonstrated the pivotal role of NB in cell transformation and survival and identified PIM1as a key downstream target of NB. These findings propose a promising therapeutic strategy for patients with NB fusion-positive leukemia.

Knockdown of PIM1 gene expression can inhibit U937 cell proliferation and promote apoptosis, in order to alleviate ALM process, which may be related to the inhibition of JAK2/STAT3 pathway activation.

These results suggested that UM171 inhibited breast cancer progression in part through activation of KLF2 and P21. Combination of UM171 with a PAN-PIM inhibitor offer a novel therapy for aggressive forms of breast cancer.

P1/2, N=240, Recruiting, Sumitomo Pharma America, Inc. | N=80 --> 240 | Trial completion date: Feb 2025 --> Apr 2030 | Trial primary completion date: Dec 2024 --> Apr 2027

PIM1 alleviated mice liver oxidative stress and NAFLD induced by High-fat diet by regulating the NRF2/HO-1/NQO1 signaling Pathway.

P1, N=60, Recruiting, Shengke Pharmaceuticals (Jiangsu) Limited, China | Trial completion date: Mar 2025 --> Jun 2026 | Trial primary completion date: Feb 2024 --> Dec 2025

P1, N=12, Completed, Sumitomo Pharma America, Inc.

The study related to their molecular interactions with receptors is also included in the present manuscript. The study may be beneficial to scientists for the development of novel compounds as PIM-1 inhibitors in the treatment of prostate cancer and leukemia.

The BRAF inhibitor vemurafenib is effective against BRAFV600E-positive PTC; however, acquired resistance to single agent therapy frequently leads to tumor recurrence and metastasis, underscoring the need to develop tailored treatment strategies...This study elucidates the role of BRAFV600E in the regulation of PIM1 in PTC and demonstrates the synergistic effect of a novel combination, BRAFi/PIMi, for the treatment of PTC. This discovery, along with the pathways that may be involved in the powerful efficacy of BRAFi/PIMi strategy from the perspective of cell metabolism, provides insight into the molecular basis of PTC progression and offers new perspectives for BRAF-resistant PTC treatment.

PIM-1 kinase inhibition was virtually elucidated by the molecular docking study, highlighting binding interactions of the lead compound 4 towards the PIM-1 protein. Accordingly, compound 4 was validated as a promising PIM-1 targeted chemotherapeutic agent to treat breast cancer.

Erastin treatment reversed the impacts of PIM1 on hRMECs, suggesting the mediation of ferroptosis in PIM1 regulation. The current study has yielded critical insights into the role of PIM1 in ameliorating high glucose-induced hRMEC dysfunction through the inhibition of ferroptosis.

Furthermore, we identified an effective synergistic combination between anwulignan and chidamide. Our findings suggested that PIM1 could be a therapeutic target and prognostic factor for DLBCL, and anwulignan holds promise for future development as a natural product for treatment.

The multivariate analysis observed the association between high lactate dehydrogenase value and the immunohistochemical expression of PIM1 or with the mutant status of the PIM1 gene representing negative prognostic factors (HR = 2.066, P = .042, respectively HR = 3.100, P = .004). In conclusion, our preliminary data suggest that the oncogenic mutations of PIM1 and MYD88 in our DLBCL cohort may improve the diagnosis and prognosis of DLBCL patients in an advanced stage.

Moreover, we also found that cerebral HP accelerated pSTAT3-mediated astrogliosis and activation of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, probably leading to cognitive decline. On the other hand, sPlas treatment attenuated the activation of the pSTAT3/PIM1/NFATc1 axis independent of RAGE and significantly suppressed NLRP3 inflammasome activation, demonstrating the beneficial effect on AD.

Kinetic studies indicated that 4c and 4f were both competitive and non-competitive inhibitors for PIM-1 kinase enzyme. In addition, in silico prediction of physiochemical properties, pharmacokinetic profile, ligand efficiency, ligand lipophilic efficiency, and induced fit docking studies were consistent with the biological and kinetic studies, and predicted that 4c and 4f could act as PIM-1 kinase competitive non-adenosine triphosphate (ATP) mimetics with drug like properties.

P1/2, N=80, Recruiting, Sumitomo Pharma America, Inc.

Compound 12 had potent cytotoxicity with IC values of 0.5 and 5.27 μM against MCF-7 and HepG2 cell lines compared with doxorubicin, which displayed the following IC: 2.14 and 2.48 μM for the mentioned cell lines, respectively...Besides, compound 12 caused tumor inhibition by 42.1% in solid tumors in the SEC-bearing mice. Results disclosed that compound 12 significantly impeded cell migration and cell proliferation by interfering with PIM-1 enzymatic activity via considerable apoptosis-induction, which made it an attractive lead compound for the development of chemotherapeutics to treat breast cancer.

Furthermore, TKO mice, lacking PIM isoforms, exhibit suppression in circulating triglycerides. Overall, our findings establish PIM1 as an important regulator of LD accumulation through GSK3β-PPARα signaling axis to promote cell proliferation and survival during nutrient stress.

In RCC cell lines, IL-6 blockade through either anti-IL-6 antibody or tocilizumab was sufficient to decrease PIM1 protein levels. Treatment with ruxolitinib leads to a dose and time-dependent decrease in PIM1 levels... These results suggest that differential expression of PIM1 in RCC may be linked to autocrine IL-6 signaling. Furthermore, poor survival in PIM1-overexpressing RCC patients is independent of treatment received, and therefore necessitates use of targeted therapies against this axis. Multiple FDA-approved agents are available that target this pathway.

PIM1 inhibitor AZD1208 was used to inhibit PIM1 and PIM1-experssing adenovirus was used to overexpress PIM1. This study demonstrated the protective effect of PIM1 in cisplatin-induced AKI, and regulation of Drp1 activation might be the underlying mechanism. Altogether, PIM1 may be a potential therapeutic target for cisplatin-induced AKI.

Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity at inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.

The most potent compounds (2d and 2 h) were tested for their antitumor effects against prostate (PC-3), colon (HCT-116), and breast (MDA-MB-231) and were evaluated in comparison to the anticancer drug tivantinib using the MTT assay...Compared to the control, compound 2d treatment significantly inhibited the protein expression levels of c-Met and Pim-1 kinases in the treated HCT-116 cells. Thorough molecular modeling analyses, such as molecular docking and dynamic simulation, were performed to ascertain the binding mechanism and stability of the target compounds.

No abstract available