Pinning down myeloma with Pim2 inhibitors!

Neri, Paola; Bahlis, Nizar J.

doi:10.1182/blood-2013-07-514091

Cited by 4 publications

(4 citation statements)

References 9 publications

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“…This up-regulation of the Pim2 gene is driven by IL6 and tumor necrosis factor (TNF) family cytokines (TNF-a, BAFF and APRIL) through signal transducer and activator of transcription 3 (STAT3) and nuclear factor kB (NK-kB) activation [51]. Treatment with Pim2 siRNA has successfully reduced MM cell proliferation [52].…”

Section: Ras/raf/mek/erkmentioning

confidence: 99%

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

Guo

McKenna

O’Dwyer

et al. 2015

Expert Opinion on Therapeutic Targets

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Section: Ras/raf/mek/erkmentioning

confidence: 99%

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

Guo

McKenna

O’Dwyer

et al. 2015

Expert Opinion on Therapeutic Targets

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“…The proviral integration site in Moloney murine leukemia virus (Pim) kinases is frequently overexpressed in multiple myeloma, and inhibition of Pim kinase activity was found to be beneficial for the treatment of multiple myeloma. − The Pim proteins are a family of constitutively active serine/threonine kinases (Pim-1, Pim-2, and Pim-3) that are highly homologous. Besides multiple myeloma, Pim kinase inhibitors are potentially useful in targeting other malignancies, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), non-Hodgkin lymphoma (NHL), and triple-negative breast cancer. − Pim kinase inhibitors are therefore highly sought after as a new cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma

Wang¹,

Blackaby

Allen

et al. 2019

J. Med. Chem.

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Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 ( 16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

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“…There are multiple isoforms of PIM2 protein (three in the mouse and potentially two in humans) due to the use of the alternative translation start codon, CTG [38] . The multiple isoforms (34 and 41 kDa) have been detected in human cells including primary leukemia cells [39] – [43] , myeloma cells [44] , [45] and lymphoma cells [46] , [47] . 34 kDa PIM2 isoform is mainly analyzed in several studies, which plays an important role in tumor progression [14] , [48] .…”

Section: Discussionmentioning

confidence: 99%

A Regulatory Feedback Loop between HIF-1α and PIM2 in HepG2 Cells

Zhao

et al. 2014

PLoS ONE

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To survive under hypoxic conditions, cancer cells remodel glucose metabolism to support tumor progression. HIF transcription factor is essential for cellular response to hypoxia. The underlying mechanism how HIF is constitutively activated in cancer cells remains elusive. In the present study, we characterized a regulatory feedback loop between HIF-1α and PIM2 in HepG2 cells. Serine/threonine kinase proto-oncogene PIM2 level was induced upon hypoxia in a HIF-1α-mediated manner in cancer cells. HIF-1α induced PIM2 expression via binding to the hypoxia-responsive elements (HREs) of the PIM2 promoter. In turn, PIM2 interacted with HIF-1α, especially a transactivation domain of HIF-1α. PIM2 as a co-factor but not an upstream kinase of HIF-1α, enhanced HIF-1α effect in response to hypoxia. The positive feedback loop between PIM2 and HIF-1α was correlated with glucose metabolism as well as cell survival in HepG2 cells. Such a regulatory mode may be important for the adaptive responses of cancer cells in antagonizing hypoxia during cancer progression.

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Pinning down myeloma with Pim2 inhibitors!

Cited by 4 publications

References 9 publications

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma

A Regulatory Feedback Loop between HIF-1α and PIM2 in HepG2 Cells

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