Pim 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition

Blanco‐Aparicio, Carmen; Collazo, Ana; Oyarzábal, Julen; Leal, Juan F.M.; Albarán, María Isabel; Lima, Francisco Ramos; Pequeño, Belén; Ajenjo, Nuria; Becerra, Mercedes; Alfonso, Patricia; Reymundo, María Isabel; Palacios, Irene; Mateos, Genoveva; Quiñones, Helena; Corrionero, Ana; Carnero, Amancio; Pevarello, Paolo; López, Ana Rodríguez; Fominaya, Jesús; Pastor, Joaquı́n; Bischoff, James R.

doi:10.1016/j.canlet.2010.09.016

Cited by 55 publications

(55 citation statements)

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“…Because no specific inhibitor of PIM2 kinases activity has been developed to date, we treated ABC-DLBCL cell lines with the small-molecule pan-PIM kinase inhibitor ETP-39010. 40,34 The IC 50 values determined for ETP-39010 was in the low micromolar range for the DLBCL cell lines (Table 2).…”

Section: Pim Pharmacologic Inhibition Induces Apoptosis and Cell-cyclmentioning

confidence: 99%

PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma

Gómez-Abad

Pisonero

Blanco‐Aparicio³

et al. 2011

Blood

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PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosaassociated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification. (Blood. 2011;118(20):5517-5527) IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common type of adult non-Hodgkin lymphoma (NHL), accounting for approximately 40% of all NHL cases. 1 Rather than being a simple entity, it encompasses a constellation of different disorders with varying clinical presentations, molecular pathogenesis, and responses to therapy. 1 Expression-profile studies have revealed the existence of several DLBCL categories, 2 reflecting their origin from discrete B-cell differentiation stages, or the coregulated expression of transcriptional signatures that reflect features of the cell of origin, molecular pathogenesis, or the microenvironment. 1,3,4 Three main subtypes can be distinguished on the basis of the cell-of-origin classification: GCB-DLBCL that express germinal center (GC) genes, activated B-like DLBCL (ABC-DLBCL) with a signature including plasma cell and NF-B-expressed genes, and primary mediastinal DLBCL. 5,6 The standard first-line therapy for treating DLBCL patients is a combination of chemotherapeutical agents (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) with the rituximab (R) chimeric CD20 monoclonal antibody. 7 Despite this therapy, the disease remains fatal in 30% to 40% of patients. 8 Novel therapeutic opportunities have been proposed based on molecular profiles, suggesting essential regulatory pathways in lymphomas (NF-B pathway, B-cell receptor signaling, B-cell lymphoma 2, B-cell lymphoma 6, and tumor microenvironment) as candidate targets. 9 Although there is a considerable amount of information about the molecular pathogenesis of DLBCL, relatively little progress has been made in developing therapies using compounds that target mutated genes or deregulated pathways. The improved knowledge about the molecular pathogenesis ...

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Section: Pim Pharmacologic Inhibition Induces Apoptosis and Cell-cyclmentioning

confidence: 99%

PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma

Gómez-Abad

Pisonero

Blanco‐Aparicio³

et al. 2011

Blood

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“…K562 cells (5. AKT inhibitors [30,46]. However, these studies lacked insights in the mechanism underlying this synergistic interaction.…”

Section: Discussionmentioning

confidence: 99%

Untitled

2016

Oncotarget

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Although conventional therapies for acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) are effective in inducing remission, many patients relapse upon treatment. Hence, there is an urgent need for novel therapies. PIM kinases are often overexpressed in AML and DLBCL and are therefore an attractive therapeutic target. However, in vitro experiments have demonstrated that intrinsic resistance to PIM inhibition is common. It is therefore likely that only a minority of patients will benefit from single agent PIM inhibitor treatment. In this study, we performed an shRNA-based genetic screen to identify kinases whose suppression is synergistic with PIM inhibition. Here, we report that suppression of p38α (MAPK14) is synthetic lethal with the PIM kinase inhibitor AZD1208. PIM inhibition elevates reactive oxygen species (ROS) levels, which subsequently activates p38α and downstream AKT/mTOR signaling. We found that p38α inhibitors sensitize hematological tumor cell lines to AZD1208 treatment in vitro and in vivo. These results were validated in ex vivo patient-derived AML cells. Our findings provide mechanistic and translational evidence supporting the rationale to test a combination of p38α and PIM inhibitors in clinical trials for AML and DLBCL.

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“…To characterize AR00460770 in vitro, the cellular half-maximal inhibitory concentration (IC 50 ) and kinase selectivity assays were determined. The cellular IC 50 of AR00460770 was analyzed by the Ser112 phosphorylation of transiently transfected Bcl-2-associated death promoter (BAD) in HEK-293 cell lines, engineered to express human Pim1 and Pim2 (Millipore, Billerica, MA) and rat Pim3 (Array BioPharma, Boulder, CO) in conjunction with a DNA vector construct directing the expression of the Pim kinase substrate glutathione S-transferase (GST)-BAD (pEBG-mBAD).…”

Section: Pim Kinase Inhibitor Treatmentmentioning

confidence: 99%

“…The cellular IC 50 and kinase selectivity of AR00460770 were determined and, as shown in Tables 1 and 2, exhibited strong inhibition specific to Pim1 kinase.…”

Section: In Vitro Characterization Of Ar00460770mentioning

confidence: 99%

Inhibition of Pim1 Kinase Activation Attenuates Allergen-Induced Airway Hyperresponsiveness and Inflammation

Shin

Takeda

Shiraishi

et al. 2012

Am J Respir Cell Mol Biol

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Pim kinases are a family of serine/threonine kinases whose activity can be induced by cytokines involved in allergy and asthma. These kinases play a role in cell survival and proliferation, but have not been examined, to the best of our knowledge, in the development of allergic disease. This study sought to determine the role of Pim1 kinase in the development of allergic airway responses. Mice were sensitized and challenged with antigen (primary challenge), or were sensitized, challenged, and rechallenged with allergen in a secondary model. To assess the role of Pim1 kinase, a small molecule inhibitor was administered orally after sensitization and during the challenge phase. Airway responsiveness to inhaled methacholine, airway and lung inflammation, cell composition, and cytokine concentrations were assessed. Lung Pim1 kinase concentrations were increased after ovalbumin sensitization and challenge. In the primary allergen challenge model, treatment with the Pim1 kinase inhibitor after sensitization and during airway challenges prevented the development of airway hyperresponsiveness, eosinophilic airway inflammation, and goblet cell metaplasia, and increased Th2 cytokine concentrations in bronchoalveolar fluid in a dose-dependent manner. These effects were also demonstrated after a secondary allergen challenge, where lung allergic disease was established before treatment. After treatment with the inhibitor, a significant reduction was evident in the number of CD4 1 and CD8 1 T cells and concentrations of cytokines in the airways. The inhibition of Pim1 kinase was effective in preventing the development of airway hyperresponsiveness, airway inflammation, and cytokine production in allergensensitized and allergen-challenged mice. These data identify the important role of Pim1 kinase in the full development of allergeninduced airway responses.

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Pim 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition

Cited by 55 publications

References 38 publications

PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma

PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma

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Inhibition of Pim1 Kinase Activation Attenuates Allergen-Induced Airway Hyperresponsiveness and Inflammation

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