Potential Use of Selective and Nonselective Pim Kinase Inhibitors for Cancer Therapy

Drygin, Denis; Haddach, Mustapha; Pierre, Fabrice; Ryckman, David M.

doi:10.1021/jm3009234

Cited by 61 publications

(34 citation statements)

References 68 publications

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“…Recent study has found that the inhibition of CK2 is correlated with radiosensitization via suppressing proliferative activity of Stat3 in NSCLC cells [56]. Blocking single radioresistant signaling used by a specific inhibitor might be, at least in part, insufficient for the regulation of radiosensitivity, because it could not be completely excluded the possibility that compensatory signaling response mediated by CK2 as a crosstalk pathway might be involved in radioresistance of NSCLC [60]. Therefore, using a dual inhibitor could be a promising strategy to enhance the efficacy of radiosensitization via blocking both radiation-associated responses at the same time.…”

Section: Discussionmentioning

confidence: 99%

PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells

Kim

Youn

Kwon

et al. 2013

Pharmacological Research

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Section: Discussionmentioning

confidence: 99%

PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells

Kim

Youn

Kwon

et al. 2013

Pharmacological Research

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“…Pim kinases possess an unusual ATP-binding pocket, widened by an insertion in the hinge region and the presence of a proline residue, which lacks one of two typically conserved residues that form backbone hydrogen bonds to the adenine ring of ATP (38)(39)(40)(41)(42). Their unusual ATP-binding sites and roles in cancer have prompted the investigation of potential Pim-selective inhibitors for cancer therapy (30,43).…”

Section: Significancementioning

confidence: 99%

Stochastic detection of Pim protein kinases reveals electrostatically enhanced association of a peptide substrate

Harrington

Cheley

Alexander

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In stochastic sensing, the association and dissociation of analyte molecules is observed as the modulation of an ionic current flowing through a single engineered protein pore, enabling the label-free determination of rate and equilibrium constants with respect to a specific binding site. We engineered sensors based on the staphylococcal α-hemolysin pore to allow the single-molecule detection and characterization of protein kinase-peptide interactions. We enhanced this approach by using site-specific proteolysis to generate pores bearing a single peptide sensor element attached by an N-terminal peptide bond to the trans mouth of the pore. Kinetics and affinities for the Pim protein kinases (Pim-1, Pim-2, and Pim-3) and cAMP-dependent protein kinase were measured and found to be independent of membrane potential and in good agreement with previously reported data. Kinase binding exhibited a distinct current noise behavior that forms a basis for analyte discrimination. Finally, we observed unusually high association rate constants for the interaction of Pim kinases with their consensus substrate Pimtide (∼10 7 to 10 8 M -1 ·s -1 ), the result of electrostatic enhancement, and propose a cellular role for this phenomenon.

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“…All 5 PIM inhibitors demonstrated significant potency against PIM1/2/3, as well as a high degree of selectivity against a panel of 192 kinases (supplemental Table 1). As depicted in Figure 1B, AML cell lines were treated with 3 structurally diverse PIM inhibitors (compound A-1, compound B-1, and compound C 29,30 ) and subsequently categorized as responders, nonresponders, or intermediates, based on the extent of their proliferative response to compounds. In parallel, the basal genomewide messenger RNA (mRNA) expression profile of each cell line was obtained and a subset of responders and nonresponders was further subjected to mechanistic studies, using 3 structurally diverse PIM inhibitors, with a focus on evaluating components of the signaling pathways PIM kinases are known to mediate.…”

Section: Identification Of Aml Cell Lines Sensitive To the Inhibitionmentioning

confidence: 99%

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

Guo

Wang

Zhang

et al. 2014

Blood

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Key Points• CD25 is a predictive biomarker for sensitivity to PIM inhibitors in AML cells.• PIM inhibitors may prolong overall/relapse-free survival through attenuating STAT5 activation and destabilizing MYC in CD25 1 AML cells.Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in

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Potential Use of Selective and Nonselective Pim Kinase Inhibitors for Cancer Therapy

Cited by 61 publications

References 68 publications

PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells

PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells

Stochastic detection of Pim protein kinases reveals electrostatically enhanced association of a peptide substrate

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

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