Pim kinase inhibitors: a survey of the patent literature

Morwick, Tina M.

doi:10.1517/13543770903496442

Cited by 69 publications

(47 citation statements)

References 68 publications

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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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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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“…ETP-39010 (4-[6-[(4-fluorophenyl)methylamino]imidazo[2,3-f]pyridazin-3-yl]phenol) was developed by the Experimental Therapeutics Program of the CNIO. 34 …”

Section: Cell Lines Cell Culture and Drugsmentioning

confidence: 99%

Section: Pim Pharmacologic Inhibition Induces Apoptosis and Cell-cyclmentioning

confidence: 99%

“…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).Increased apoptosis was detected after 24 to 48 hours by annexin V ϩ and PI staining. A time-dependent increase in the population of apoptotic cells was observed in all cell lines ( Figure 3A).…”

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confidence: 97%

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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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“…LGB321 is unique relative to previously described PIM inhibitors (10)(11)(12)(13), in that it is active in PIM2-dependent cell lines (14), a kinase that has proven difficult to inhibit in the cellular context. Consistent with its activity on all three PIM kinases, LGB321 inhibits proliferation of a number of cell lines derived from diverse hematologic malignancies, including multiple myeloma, AML, CML, and B-cell NHL.…”

Section: Introductionmentioning

confidence: 99%

Pan-PIM Kinase Inhibition Provides a Novel Therapy for Treating Hematologic Cancers

García

Langowski

Wang

et al. 2014

Clinical Cancer Research

107

112

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Purpose: PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematologic cancers. Consistent with this, we found that PIMs are highly expressed in human hematologic cancers and show that each isoform has a distinct expression pattern among disease subtypes. This suggests that inhibitors of all three PIMs would be effective in treating multiple hematologic malignancies.Experimental Design: Pan-PIM inhibitors have proven difficult to develop because PIM2 has a low K m for ATP and, thus, requires a very potent inhibitor to effectively block the kinase activity at the ATP levels in cells. We developed a potent and specific pan-PIM inhibitor, LGB321, which is active on PIM2 in the cellular context.Results:LGB321 is active on PIM2-dependent multiple myeloma cell lines, where it inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling of LGB321 demonstrates limited activity in cell lines derived from solid tumors. In contrast, significant activity in cell lines derived from diverse hematological lineages was observed, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma and non-Hodgkin lymphoma (NHL). Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, in which modulation of pharmacodynamics markers is predictive of efficacy. Finally, we demonstrate that LGB321 synergizes with cytarabine in this model. Conclusions:We have developed a potent and selective pan-PIM inhibitor with single-agent antiproliferative activity and show that it synergizes with cytarabine in an AML xenograft model. Our results strongly support the development of Pan-PIM inhibitors to treat hematologic malignancies.

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Pim kinase inhibitors: a survey of the patent literature

Cited by 69 publications

References 68 publications

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

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

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

Pan-PIM Kinase Inhibition Provides a Novel Therapy for Treating Hematologic Cancers

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