Pim Rajjayabun
Ontology highlight
ABSTRACT:
SUBMITTER: Rajjayabun P
PROVIDER: S-EPMC1121965 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma. 5-(3-Trifluoromethylbenzylidene)thiazolidine-2,4-dione (4a) was identified by screening to be a Pim-1 inhibitor and was found to attenuate the autophosphorylation of tagged Pim-1 in intact cells. Although 4a is a competitive inhibitor with respect to ATP, a screen of approximately 50 diverse protein kinases demonstrated that it has high selectivity for Pim kinases. Computational docking of 4a to Pim-1 provided a model for lead optimization, and a series of substituted thiazolidine-2,4-dione congeners was synthesized. The most potent new compounds exhibited IC(50)s of 13 nM for Pim-1 and 2.3 microM for Pim-2. Additional compounds in the series demonstrated selectivities of more than 2500-fold and 400-fold for Pim-1 or Pim-2, respectively, while other congeners were essentially equally potent toward the two isozymes. Overall, these compounds are new Pim kinase inhibitors that may provide leads to novel anticancer agents.
| S-EPMC5404933 | biostudies-literature
Project description:BACKGROUND: Pim family kinases are small constitutively active serine/threonine-specific kinases, elevated levels of which have been detected in human hematopoietic malignancies as well as in solid tumours. While we and others have previously shown that the oncogenic Pim kinases stimulate survival of hematopoietic cells, we now examined their putative role in regulating motility of adherent cancer cells. For this purpose, we inhibited Pim kinase activity using a small molecule compound, 1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde (DHPCC-9), which we had recently identified as a potent and selective inhibitor for all Pim family members. RESULTS: We now demonstrate that the Pim kinase inhibitor DHPCC-9 is very effective also in cell-based assays. DHPCC-9 impairs the anti-apoptotic effects of Pim-1 in cytokine-deprived myeloid cells and inhibits intracellular phosphorylation of Pim substrates such as Bad. Moreover, DHPCC-9 slows down migration and invasion of cancer cells derived from either prostate cancer or squamocellular carcinoma patients. Silencing of Pim expression reduces cell motility, while Pim overexpression enhances it, strongly suggesting that the observed effects of DHPCC-9 are dependent on Pim kinase activity. Interestingly, DHPCC-9 also abrogates NFATc-dependent migration of cancer cells, implying that NFATc factors mediate at least part of the pro-migratory effects of Pim kinases. CONCLUSIONS: Altogether, our data indicate that DHPCC-9 is not only a powerful tool to investigate physiological effects of the oncogenic Pim family kinases, but also an attractive molecule for drug development to inhibit invasiveness of Pim-overexpressing cancer cells.
| S-EPMC2978147 | biostudies-literature
Project description:Branched forms of the archetypal polymer of intrinsic microporosity PIM-1 and the pyridinecarbonitrile-containing PIM-Py may be crosslinked under ambient conditions by palladium(II) acetate. Branched PIM-1 can arise in polymerizations of 5,5',6,6'-tetrahydroxy-3,3,3',3'-tetramethyl-1,1'-spirobisindane with tetrafluoroterephthalonitrile conducted at a high set temperature (160 °C) under conditions, such as high dilution, that lead to a lower-temperature profile over the course of the reaction. Membranes of PIM-1 and PIM-Py crosslinked with palladium acetate are sufficiently stable in organic solvents for use in the recovery of toluene from its mixture with dimethyl sulfoxide (DMSO) by pervaporation at 65 °C. With both PIM-1 and PIM-Py membranes, pervaporation gives high toluene/DMSO separation factors (around 10 with a 77 vol % toluene feed). Detailed analysis shows that the membranes themselves are slightly selective for DMSO and it is the high driving force for toluene evaporation that drives the separation.
| S-EPMC9926464 | biostudies-literature
Project description:Human HCC cell line, MHCC-97L, was subcutaneously injected to BALB/c nude mice. Two weeks post injection, mice were randomised to receive vehicle or PIM447 (60mg/kg) by oral gavage three times a week for two weeks. Total RNA was extracted from the tumor xenograft (Vehicle, n=2; PIM447, n=2) and subjected to RNA sequencing. Expression profiling of the tumors between vehicle control and PIM447 treated groups was compared.
2020-06-03 | GSE142871 | GEO
Project description:Host signal-transduction pathways are intimately involved in the switch between latency and productive infection of herpes viruses. As with other herpes viruses, infection by Kaposi's sarcoma herpesvirus (KSHV) displays these two phases. During latency only few viral genes are expressed, while in the productive infection the virus is reactivated with initiation of extensive viral DNA replication and gene expression, resulting in production of new viral particles. Viral reactivation is crucial for KSHV pathogenesis and contributes to the progression of KS. We have recently identified Pim-1 as a kinase reactivating KSHV upon over-expression. Here we show that another Pim family kinase, Pim-3, also induces viral reactivation. We demonstrate that expression of both Pim-1 and Pim-3 is induced in response to physiological and chemical reactivation in naturally KSHV-infected cells, and we show that they are required for KSHV reactivation under these conditions. Furthermore, our data indicate that Pim-1 and Pim-3 contribute to viral reactivation by phosphorylating the KSHV latency-associated nuclear antigen (LANA) on serine residues 205 and 206. This counteracts the LANA-mediated repression of the KSHV lytic gene transcription. The identification of Pim family kinases as novel cellular regulators of the gammaherpesvirus life cycle facilitates a deeper understanding of virus-host interactions during reactivation and may represent potential novel targets for therapeutic intervention.
| S-EPMC2648312 | biostudies-literature
Project description:Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.
| S-EPMC4526774 | biostudies-literature
Project description:The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases is serine/threonine kinases that promote growth and survival in multiple cell types, implicated in the pathogenesis of various diseases. Over expression of Pim-1 experimentally leads to tumor formation in mice, whereas there is no observable phenotype concerning the complete knockout of the protein. When it is over expressed it may lead to cancer development by three major ways; by inhibiting apoptosis, by promoting cell proliferation and also through promoting genomic instability. Expression in normal tissues is nearly undetectable. Recent improvements in the development of novel inhibitors of PIMs have been reviewed. Significant progress in the design of PIMs inhibitors, in which it displays selectivity versus other kinases, has been achieved within the last years. However, the development of isoform-selective PIM inhibitors is still an open task. As Pim-1 possesses oncogenic functions and is over expressed in various kinds of cancer diseases, its inhibition provides a new option in cancer therapy. A PubMed literature search was performed to review the currently available data on Pim-1 expression, regulation, and targets; its implication in different types of cancer and its impact on prognosis is described. Consequently, designing new inhibitors of PIMs is now a very active area of research in academic and industrial laboratories.
| S-EPMC6651028 | biostudies-literature
Project description:PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity in 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.
2023-12-04 | GSE237256 | GEO