Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation

Lü, Jing; Zavorotinskaya, Tatiana; Dai, Yumin; Niu, Xiaohong; Castillo, Joseph; Sim, Janet; Yu, Jianjun; Wang, Yingyun; Langowski, John L.; Holash, Jocelyn; Shannon, Kevin; García, Pablo D.

doi:10.1182/blood-2013-01-481457

Cited by 160 publications

(219 citation statements)

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“…For example, in the multiple myeloma derived KMS-11 luc cell line with high expression levels of PIM2, compound 5c inhibits phosphorylation of pBAD Ser112 (a direct substrate) at 10 nM, inhibits phosphorylation of pS6RP Ser240/4 (a downstream substrate) at 38 nM and inhibits cell proliferation at 17 nM. 12 The large upward potency shift in going from the enzyme to cells was consistent with the low ATP K m for PIM2. 20 In comparison, SGI1776 and AZD1208 inhibit cell proliferation in the KMS-11luc cell line at 4500 and 680 nM, respectively.…”

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confidence: 85%

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Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors

Burger¹,

Han²,

Lan³

et al. 2013

ACS Med. Chem. Lett.

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Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, nonHodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM K i s < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pimdependent tumor model is described. KEYWORDS: Proviral insetion site in Moloney murine leukemia virus kinases inhibitors, Pim1 kinase inhibitor, Pim2 kinase inhibitor, Pim3 kinase inhibitor, pan-Pim kinase inhibitors P roviral insertion site of Moloney murine leukemia virus kinases, or PIM 1, 2, and 3 kinases are constitutively active serine/threonine kinases that normally function in the survival, proliferation, and differentiation of hematopoietic cells in response to growth factors and cytokines. 1,2 PIM's play redundant roles in oncogenesis and, therefore, suggest that a pan-PIM kinase inhibitor may be clinically useful. 3 In human disease, high expression and/or dysfunction of the three PIMs has been implicated in the progression of hematopoetic and solid tumor cancers. 1,2 In addition to cancer, PIM kinases have been reported to play a role in several autoimmune diseases. 4 Not surprisingly, PIM kinases have emerged as attractive therapeutic targets and have elicited several groups to investigate and report novel inhibitors of PIM 5−10 including the clinical compounds SGI-1776 6 and AZD1208, 7 Figure 1. Pim kinases share a high level of sequence homology within the family (>61%) and all share the unique feature of being the only kinases with a proline in the hinge, 11 which results in only one hydrogen bond interaction with ATP. As the ATP K m for PIM2 is 10−100× lower than that for PIM1 and PIM3, cell active pan PIM inhibitors have been more challenging to identify than PIM 1/3 inhibitors. Herein, we describe potent and selective cell active inhibitors of all three PIM kinases. A representative of this compound series, 5c, has suitable PK properties and was recently used to establish a PK/PD efficacy relationship in a PIM2 driven multiple myeloma xenograft model. 12 Here we also demonstrate efficacy in the AML EOL-1 xenograft model. Letter pubs.acs.org/acsmedchemlett

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confidence: 85%

“…12 Continual modulation of target, as judged by pS6RP inhibition, was associated with maximal efficacy. In addition to antitumor activity in the multiple myeloma model, here we demonstrate efficacy in the EOL-1 acute myeloid leukemia xenograph model.…”

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confidence: 97%

Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors

Burger¹,

Han²,

Lan³

et al. 2013

ACS Med. Chem. Lett.

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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.…”

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confidence: 99%

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

García

Langowski

Wang

et al. 2014

Clinical Cancer Research

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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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“…Alternatively, Pims could regulate mTORC1 activity in AML through upstream regulation of the mTORC1 negative regulator TSC2 ( Figure 3A), as recently demonstrated in multiple myeloma models. 37 Ongoing preclinical and clinical analyses will be required to better understand the mechanism of action and context dependency of Pim kinase inhibition. The pan-Pim potency and selectivity of AZD1208 render it a particularly useful pharmacologic tool for such studies.…”

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confidence: 99%

AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

Keeton

McEachern

Dillman

et al. 2014

Blood

222

216

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Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation

Cited by 160 publications

References 50 publications

Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors

Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors

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

AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

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