Pim-1 Kinase Research Articles

PIM1 phosphorylates ABI2 to enhance actin dynamics and promote tumor invasion.

Distinguishing key factors that drive the switch from indolent to invasive disease will make a significant impact on guiding the treatment of prostate cancer (PCa) patients. Here, we identify a novel signaling pathway linking hypoxia and PIM1 kinase to the actin cytoskeleton and cell motility. An unbiased proteomic screen identified Abl-interactor 2 (ABI2), an integral member of the wave regulatory complex (WRC), as a PIM1 substrate. Phosphorylation of ABI2 at Ser183 by PIM1 increased ABI2 protein levels and enhanced WRC formation, resulting in increased protrusive activity and cell motility. Cell protrusion induced by hypoxia and/or PIM1 was dependent on ABI2. In vivo smooth muscle invasion assays showed that overexpression of PIM1 significantly increased the depth of tumor cell invasion, and treatment with PIM inhibitors significantly reduced intramuscular PCa invasion. This research uncovers a HIF-1-independent signaling axis that is critical for hypoxia-induced invasion and establishes a novel role for PIM1 as a key regulator of the actin cytoskeleton.

Abstract 5791: Autophagy & PIM1 kinase inhibition in breast cancer stem cells & bulk cancer cells attenuates breast cancer & metastasis

Abstract Autophagy is a self-degradation process, it is essential for growth of heterogenous of breast cancer cells. Breast tumor heterogeneity majorly comprises bulk cancer cells & cancer stem cells (CSCs). Targeting either CSCs or cancer cells could lead to interconversion between these cells due to EMT/MET transitions. Therefore, it is important to identify a common molecular targets & its mechanism of regulation in these populations for improvement of breast cancer therapy. Here, we utilized a PCR based screen & identified NUMA1 downregulation in FIP200 KO (autophagy gene) cells of three major breast cancer subtypes, FF99 (luminal), N418 (Her2+) & BF3M (basal). Further, NUMA1 KO in these cells reduced tumor formation & CSCs indicating the role of NUMA1 on regulation of CSCs. Therefore, we sorted breast CSCs, ALDH+ and CD29hi CD61+ from WT & NUMA1 KO cells, tail-vein injected nude mice depicted reduced metastatic potential with NUMA1 KO than WT CSCs. Mechanistically, NUMA1 regulation by PIM1 kinase was observed in CSCs but not in bulk cancer cells. Cell viability assays revealed that combination treatment of autophagy & PIM1 inhibitor showed higher efficacy against cancer cells of three breast cancer subtypes than individual treatments alone. Finally, the combination treatment of autophagy inhibitor, Lys05 & PIM1 inhibitor, SMI-4a reduced tumor formation & metastasis of breast cancer. Human tissue microarray results depicted high expression of NUMA1 & PIM1 in different breast cancer subtypes than non- tumor tissues. Our study demonstrated that inhibition of autophagy & PIM1 in bulk cancer cells & CSCs showed attenuation of tumor formation & metastasis, suggesting this combination treatment serves as an important therapeutic approach for treating breast cancer. Citation Format: Kanakaraju Manupati, Mingang Hao, Michael Haas, Syn Kok Yeo, Jun-Lin Guan. Autophagy & PIM1 kinase inhibition in breast cancer stem cells & bulk cancer cells attenuates breast cancer & metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5791.

In-Silico Prediction of Phytoconstituents from Phyllanthus niruri for Anticancer Activity against Prostate Cancer Targeting PIM-1 Kinase

Objective: Lung cancer, commonly referred to as lung carcinoma, is a malignant tumour of the lung that is characterised by unchecked cell proliferation in lung tissues.Oncemore, medicinal plants are being researched for the treatment of lung cancer. Prototypical compounds found in medicinal plants have been the source of many conventional medications. In-silico testing of Phyllanthus niruri (L.) Lour. phytoconstituents for anticancer efficacy was a part of our investigation. Design: Utilizing Discovery studio, molecular docking is done to assess the pattern of interaction between the phytoconstituents from the Phyllanthus niruri plant and the crystal structure of the anticancer proteins (PDB ID: 3A99). Later, SwissADME and pkCSM were used to screen for toxicity as well as the pharmacokinetic profile. Results: The docked results suggest that luteolin (-8.3 kcal/mol), and caffeic acid (-6.6 kcal/mol), for 3A99 macromolecule has best binding affinity towards PIM-1 kinase for anticancer activity on lungs as compared to the standard drug lenvatinib mesylate (-3.5 kcal/mol). Furthermore, pharmacokinetics and toxicity parameters were within acceptable limits according to ADMET studies. Conclusion: Results from the binding potential of phytoconstituents aimed at anticancer activity were encouraging. It promotes the usage of Phyllanthus niruri and offers crucial details on pharmaceutical research and clinical care.

CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma

Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.

Novel antimyeloma therapeutic option with inhibition of the HDAC1-IRF4 axis and PIM kinase.

Multiple myeloma (MM) preferentially expands and acquires drug resistance in the bone marrow (BM). We herein examined the role of histone deacetylase 1 (HDAC1) in the constitutive activation of the master transcription factor IRF4 and the prosurvival mediator PIM2 kinase in MM cells. The knockdown or inhibition of HDAC1 by the class I HDAC inhibitor MS-275 reduced the basal expression of IRF4 and PIM2 in MM cells. Mechanistically, the inhibition of HDAC1 decreased IRF4 transcription through histone hyperacetylation and inhibiting the recruitment of RNA polymerase II at the IRF4 locus, thereby reducing IRF4-targeting genes, including PIM2. In addition to the transcriptional regulation of PIM2 by the HDAC1-IRF4 axis, PIM2 was markedly upregulated by external stimuli from BM stromal cells and interleukin-6 (IL-6). Upregulated PIM2 contributed to the attenuation of the cytotoxic effects of MS-275. Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and invivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in the BM.

Neoprzewaquinone A Inhibits Breast Cancer Cell Migration and Promotes Smooth Muscle Relaxation by Targeting PIM1 to Block ROCK2/STAT3 Pathway

Salvia miltiorrhiza Bunge (Danshen) has been widely used to treat cancer and cardiovascular diseases in Chinese traditional medicine. Here, we found that Neoprzewaquinone A (NEO), an active component of S. miltiorrhiza, selectively inhibits PIM1. We showed that NEO potently inhibits PIM1 kinase at nanomolar concentrations and significantly suppresses the growth, migration, and Epithelial-Mesenchymal Transition (EMT) in the triple-negative breast cancer cell line, MDA-MB-231 in vitro. Molecular docking simulations revealed that NEO enters the PIM1 pocket, thereby triggering multiple interaction effects. Western blot analysis revealed that both NEO and SGI-1776 (a specific PIM1 inhibitor), inhibited ROCK2/STAT3 signaling in MDA-MB-231 cells, indicating that PIM1 kinase modulates cell migration and EMT via ROCK2 signaling. Recent studies indicated that ROCK2 plays a key role in smooth muscle contraction, and that ROCK2 inhibitors effectively control the symptoms of high intraocular pressure (IOP) in glaucoma patients. Here, we showed that NEO and SGI-1776 significantly reduce IOP in normal rabbits and relax pre-restrained thoracic aortic rings in rats. Taken together, our findings indicated that NEO inhibits TNBC cell migration and relaxes smooth muscles mainly by targeting PIM1 and inhibiting ROCK2/STAT3 signaling, and that PIM1 may be an effective target for IOP and other circulatory diseases.

Combining machine learning and structure-based approaches to develop oncogene PIM kinase inhibitors.

Introduction: PIM kinases are targets for therapeutic intervention since they are associated with a number of malignancies by boosting cell survival and proliferation. Over the past years, the rate of new PIM inhibitors discovery has increased significantly, however, new generation of potent molecules with the right pharmacologic profiles were in demand that can probably lead to the development of Pim kinase inhibitors that are effective against human cancer. Method: In the current study, a machine learning and structure based approaches were used to generate novel and effective chemical therapeutics for PIM-1 kinase. Four different machine learning methods, namely, support vector machine, random forest, k-nearest neighbour and XGBoost have been used for the development of models. Total, 54 Descriptors have been selected using the Boruta method. Results: SVM, Random Forest and XGBoost shows better performance as compared to k-NN. An ensemble approach was implemented and, finally, four potential molecules (CHEMBL303779, CHEMBL690270, MHC07198, and CHEMBL748285) were found to be effective for the modulation of PIM-1 activity. Molecular docking and molecular dynamic simulation corroborated the potentiality of the selected molecules. The molecular dynamics (MD) simulation study indicated the stability between protein and ligands. Discussion: Our findings suggest that the selected models are robust and can be potentially useful for facilitating the discovery against PIM kinase.

Role and mechanism of PIM family in the immune microenvironment of diffuse large B cell lymphoma

BackgroundDiffuse large B cell lymphoma (DLBCL) is a more common non-Hodgkin lymphoma (NHL). This study aims to explore the prognostic value of PIM kinase family in DLBCL and its relationship with the immune microenvironment, to provide a certain reference for the prognosis and treatment of DLBCL.MethodsThe prognostic value of PIM kinase family in DLBCL from the data set GSE10846 was verified through survival analysis and cox regression analysis. Mutations in PIM kinase family and its relationship with immune cell infiltration were explored with online cBioPortal, TIMER database, and single-gene GSEA analysis. Finally, the expression of PIM kinase family in tissues from DLBCL clinical samples was validated through immunohistochemical staining.ResultsThe proteins of PIM kinase family were highly expressed in DLBCL patients, which are good prognostic factors for DLBCL patients. Then, PIM1-3 proteins were positively correlated with the immune infiltration of B cells, whose types of mutations also showed different degrees of correlation with B cells. PIM kinase family proteins also showed a high correlation with PDL1. In addition, PIM kinase family was also associated with the commonly mutated genes in DLBCL, such as MYD88, MYC, and BTK.ConclusionPIM kinase family may be a potential therapeutic target for DLBCL patients.

Design, Synthesis and Biological Evaluation of Novel Quinoline Derivatives as Potential Anti-Proliferative Agents Against PC-3 and KG-1 Cells.

Cancer is a major public health problem worldwide, and is the leading cause of death. The discovery and development of cancer therapeutic drugs have become the most urgent measure, which significantly benefited from the usage of small molecule compounds. The quinoline core possessed a vast number of biological activities that were found to be imperative. The aim is to design, synthesize and perform the biological evaluation of novel quinoline derivatives as potential anti-proliferative agents. Quinoline as a privileged scaffold was adopted to introduce diverse effective nitrogen heterocycles through different linkers. The synthesized compounds were spectroscopically characterized and evaluated for their anti-proliferative activity using the CCK8 assay. The mechanism of action was investigated by flow cytometry and the inhibitory activity against Pim-1 kinase was measured by mobility shift assay. Molecular docking analysis was performed to rationalize biochemical potency as well. The majority of these quinolines displayed potent growth inhibitory effects, among which compounds 13e, 13f and 13h were the most effective ones, with GI50 values of 2.61/3.56, 4.73/4.88 and 4.68/2.98 μM, respectively. Structure-activity relationships indicated that both appropriate heterocycles at the C4 position of pyridine and suitable substituent at quinoline had a significant impact on improving activity. Compounds 13e and 24d exhibited moderate Pim-1 kinase inhibitory activity. In this study, three series of novel molecules bearing quinoline scaffold were designed, synthesized and evaluated for their in-vitro anti-proliferative activity. The most promising candidate, 13e, caused cell cycle arrest in a concentration-dependent manner and further induced apoptosis, which might represent a novel antiproliferative agent working through Pim-1 kinase inhibition to a certain extent.

A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal enzyme in the Toll-like receptor (TLR)/MYD88 dependent signaling pathway, which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction invitro and invivo. In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs. In addition, KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.

Discovery of PIM-1 kinase inhibitors based on the 2,5-disubstituted 1,3,4-oxadiazole scaffold against prostate cancer: Design, synthesis, in vitro and in vivo cytotoxicity investigation

PIM-1 kinases play an established role in prostate cancer development and progression. This research work tackles the design and synthesis of new PIM-1 kinase targeting 2,5-disubstituted-1,3,4-oxadiazoles 10a-g&11a-f, and investigation thereof as potential anti-cancer agents through in vitro cytotoxicity assay followed by in vivo studies along with exploration of this chemotype's plausible mechanism of action. In vitro cytotoxicity experiments have disclosed 10f as the most potent derivative against PC-3 cells (IC50 = 16 nM) compared to the reference drug Staurosporine (IC50 = 0.36 μM), also eliciting good cytotoxicity against HepG2 and MCF-7 cells (IC50 = 0.13 and 5.37 μM, respectively). Investigating PIM-1 kinase inhibitory activity of compound 10f revealed an IC50 of 17 nM paralleled to that of Staurosporine (IC50 = 16.7 nM). Furthermore, compound 10f displayed an antioxidant activity eliciting a DPPH inhibition ratio of 94% as compared to Trolox (96%). Further investigation demonstrated that 10f induced apoptosis in treated PC-3 cells by 43.2-fold (19.44%) compared to 0.45% in control. 10f also disrupted the PC-3 cell cycle by increasing the cell population at the PreG1-phase by 19.29-fold while decreasing the G2/M-phase by 0.56-fold compared to control. Moreover, 10f affected a downregulation of JAK2, STAT3 and Bcl-2 and upregulation of caspases 3, 8 and 9 levels that activated the caspase-dependent apoptosis. Finally, in vivo 10f-treatment caused a significant increase in tumor inhibition by 64.2% compared to 44.5% in Staurosporine treatment of the PC-3 xenograft mouse model. Additionally, it improved the hematological, biochemical parameters, and histopathological examinations compared to control untreated animals. Finally, docking of 10f with the ATP-binding site of PIM-1 kinase demonstrated good recognition of and effective binding to the active site. In conclusion, compound 10f represents a promising lead compound that merits further future optimization for controlling prostate cancer.

Inhibition of PIM Kinases Promotes Neuroblastoma Cell Differentiation to a Neuronal Phenotype

BackgroundNeuroblastoma arises from aberrancies in neural stem cell differentiation. PIM kinases contribute to cancer formation, but their precise role in neuroblastoma tumorigenesis is poorly understood. In the current study, we evaluated the effects of PIM kinase inhibition on neuroblastoma differentiation. MethodsVersteeg database query assessed the correlation between PIM gene expression and the expression of neuronal stemness markers and relapse free survival. PIM kinases were inhibited with AZD1208. Viability, proliferation, motility were measured in established neuroblastoma cells lines and high-risk neuroblastoma patient-derived xenografts (PDXs). qPCR and flow cytometry detected changes in neuronal stemness marker expression after AZD1208 treatment. ResultsDatabase query showed increased levels of PIM1, PIM2, or PIM3 gene expression were associated with higher risk of recurrent or progressive neuroblastoma. Increased levels of PIM1 were associated with lower relapse free survival rates. Higher levels of PIM1 correlated with lower levels of neuronal stemness markers OCT4, NANOG, and SOX2. Treatment with AZD1208 resulted in increased expression of neuronal stemness markers. ConclusionsInhibition of PIM kinases differentiated neuroblastoma cancer cells toward a neuronal phenotype. Differentiation is a key component of preventing neuroblastoma relapse or recurrence and PIM kinase inhibition provides a potential new therapeutic strategy for this disease.

Design, synthesis and cytotoxic evaluation of novel bis-thiazole derivatives as preferential Pim1 kinase inhibitors with in vivo and in silico study

Bis-thiazole derivatives were synthesised conforming to the Pim1 pharmacophore model following Hantzsch condensation. Pim1 has a major role in regulating the G1/S phase which upon inhibition the cell cycle stops at its early stages. Derivatives 3b and 8b showed the best Pim1 IC50 0.32 and 0.24 µM, respectively relative to staurosporine IC50 0.36 µM. Further confirmation of 3b and 8b Pim1 inhibition was implemented by hindering the T47D cell cycle at G0/G1 and S phases where 3b showed 66.5% cells accumulation at G0/G1 phase while 8b demonstrated 26.5% cells accumulation at the S phase compared to 53.9% and 14.9% of a control group for both phases, respectively. Additional in vivo cytotoxic evaluation of 3b and 8b revealed strong antitumor activity with up-regulation of caspase-3 and down-regulation of VEGF and TNF α immune expression with concomitant elevation of malondialdehyde levels in case of 8b.

Discovery of new pyridine-quinoline hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities

New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b, 5c, 6e, 13a, 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver–Burk double-reciprocal plot indicated that 5b, 5c, 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases.

Duplicate genes as sources for rapid adaptive evolution of sperm under environmental pollution in tree sparrow.

Environmental pollution can result in poor sperm quality either directly or indirectly in birds. However, adaptive and compensatory sperm morphology changes and motility improvements have rapidly evolved in tree sparrows (Passer montanus) inhabiting polluted areas over the past 65 years. To identify the genetic underpinnings of the rapidly evolving sperm phenotype, we carried out population genomics and transcriptomics on tree sparrow populations in the two differently polluted places. We identified a gene encoding the serine/threonine protein kinase PIM1, which may drive rapid phenotypic evolution of sperm. An unprecedented and remarkable expansion of the PIM gene family, caused by tandem and segmental duplication of PIM1, was subsequently observed in the tree sparrow genome. Most PIM1 duplicates showed a testis-specific expression pattern, suggesting that their functions are related to male reproduction. Furthermore, the elevated expression level of PIM1 was consistent with our earlier findings of longer and faster swimming sperm in polluted sites, indicating an important role for duplicated PIM1 in facilitating the rapid evolution of sperm. Our results suggest that duplicated PIM1 provides sources of genetic variation that may enable the rapid evolution of sperm under environmental heavy metal pollution. The findings of this study indicated that duplicated genes can be targets of selection and predominant sources for rapid adaptation to environmental change and shed light on sperm evolution under pollution stress.

Spectrochemical, biological, and toxicological studies of DDT, DDD, and DDE: An in-silico approach

Pesticides are used to control the various pests and disease carriers. Degradation and/or biotransformation alter their chemical and toxicological nature. An attempt has been taken to investigate the physicochemical, spectral, and toxicological nature of DDT [1, 1'-(2, 2, 2-trichloroethylidene) bis(4-chlorobenzene)] and its major derivatives. DDT is transformed into DDD [l, l-dichloro-2, 2-bis(p,p-chlorophenylethane)], and DDE [l, l-dichloro-2, 2-bis(p,p-chlorophenylethylene)] under reductive dechlorination conditions. They last longer in the fatty tissue due to fat-soluble features, and exhibit some harmful effects on the environment and biological systems. Herein, density functional theory along with the CAM-B3LYP/6-311g ++ (d, p) basis set has been employed to investigate their physicochemical, and spectral properties. In-silico methods were incorporated to evaluate their biological, and toxicological properties. Molecular docking and nonbonding interaction calculations were performed to investigate their binding properties and mode(s) of action against the human estrogen receptor (PDB ID: 6PYF), and serine/threonine-protein kinase PIM-2 (PDB ID: 2IWI). Further, molecular dynamics simulation was performed to check the deformability and interactions of protein and amino acid residues, respectively. ADMET (absorption, distribution, metabolism, excretion, and toxicity) and PASS (prediction of activity spectra for substances) predictions were performed to compare their biological and toxicological properties. DDT has the highest free energy, dipole moment, and chemical reactivity; meanwhile, DDE and DDD have the highest binding affinity against both proteins. All the compounds exhibit hepato-toxicological, neuro-toxicological, and carcinogenic properties which depict their toxicological level. Based on their studied parameters, this study can help to increase awareness and provide a deeper understanding of the biochemical, and toxicological impacts on the environment and biological system.

Pim-2 Kinase Regulates Energy Metabolism in Multiple Myeloma

Pim-2 kinase is overexpressed in multiple myeloma (MM) and is associated with poor prognosis in patients with MM. Changes in quantitative metabolism, glycolysis, and oxidative phosphorylation pathways are reportedly markers of all tumor cells. However, the relationship between Pim-2 and glycolysis in MM cells remains unclear. In the present study, we explored the relationship between Pim-2 and glycolysis. We found that Pim-2 inhibitors inhibited glycolysis and energy production in MM cells. Inhibition of Pim-2 decreased the proliferation of MM tumor cells and increased their susceptibility to apoptosis. Our data suggest that reduced Pim-2 expression inhibits the energy metabolism process in MM, thereby inhibiting tumor progression. Hence, Pim-2 is a potential metabolic target for MM treatment.

Recent Research Advances in Small-Molecule Pan-PIM Inhibitors

PIM kinase is consequently emerging as a promising target for cancer therapeutics and immunomodulation. PIM kinases are overexpressed in a variety of hematological malignancies and solid tumors, and their inhibition has become a strong therapeutic interest. Currently, some pan-PIM kinase inhibitors are being developed under different phases of clinical trials. Based on the different scaffold structures, they can be classified into various subclasses. The X-ray structure of the kinase complex outlines the rationale of hit compound confirmation in the early stage. Structure–activity relationships allow us to rationally explore chemical space and further optimize multiple physicochemical and biological properties. This review focuses on the discovery and development of small-molecule pan-PIM kinase inhibitors in the current research, and hopes to provide guidance for future exploration of the inhibitors.

Aberrant metabolic processes promote the immunosuppressive microenvironment in multiple myeloma.

Multiple myeloma (MM) is still an incurable plasma cell malignancy. The efficacy of immunotherapy on MM remains unsatisfactory, and the underlying molecular mechanisms still are not fully understood. In this study, we delineated the dynamic features of immune cell in MM bone marrow (BM) along with elevated tumor cell infiltration by single-cell RNA sequencing (scRNA-seq), and investigated the underlying mechanisms on dysfunction of immune cells associated with myelomagenesis. We found that immune cells were activated in those patients with low infiltration of tumor cells, meanwhile suppressed with elevated infiltration of MM cells, which facilitated MM escaping from immune surveillance. Besides PD-1, abnormal expression of PIM kinases, KLRB1 and KLRC1 were involved in the defect of immune cells in MM patients. Importantly, we found aberrant metabolic processes were associated with the immunosuppressive microenvironment in MM patients. Disordered amino acid metabolism promoted the dysfunction of cytotoxicity CD8 T cells as well as lipid metabolism disorder was associated with the dysregulation of NK and DCs in MM. As metabolic checkpoints, PIM kinases would be potential effective strategies for MM immunotherapy. In summary, redressing the disordered metabolism should be the key points to get promising effects in immune-based therapies.

Identification of protein kinase C beta as a therapeutic target for neuroendocrine prostate cancer and development of a nanoparticle-based therapeutic strategy

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of malignant prostate cancer for which there is no effective treatment. Although protein kinases are the most attractive therapeutic targets for cancer treatment, there are no clear kinase-targeted drugs available for NEPC treatment. Herein, we showed that protein kinase C beta (PKCβ) is highly expressed in NEPC and can be transcriptionally activated by c-Myc through the E-box elements present in its promoter region. Furthermore, PKCβ can activate PIM1 kinase by phosphorylating Ser51 and Ser54, which in turn stabilizes and enhances c-Myc function. Three formed a PIM1-c-Myc-PKCβ positive feedback loop to promote the progression of NEPC. Enzastaurin, a specific inhibitor of PKCβ, significantly ameliorated NEPC. However, enzastaurin causes thrombus and other side effects in several clinical trials of other diseases, which greatly limits its clinical application. To address these problems, we developed a functional polymer nanoparticle modified with SSTR2-targeted octreotide and a thrombin-binding aptamer to deliver enzastaurin for NEPC treatment. The tailor-designed nanomedicine efficiently retards tumor growth and the incidence of coagulation abnormalities in vitro and in vivo. Collectively, our findings highlight the key role of PKCβ in NEPC and provide a promising nanoparticle-based therapeutic strategy for the treatment of NEPC.