Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCβ

Faul, Margaret M.; Gillig, James R.; Jirousek, Michael R.; Ballas, Lawrence M.; Schotten, Theo; Kahl, Astrid; Möhr, Michael

doi:10.1016/s0960-894x(03)00286-5

Cited by 89 publications

(70 citation statements)

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“…One of the most promising PKC inhibitors for melanoma is Enzastaurin (LY317615.HCl), a PKCb-selective, orally available ATP analog that has shown some activity against melanoma in pre-clinical studies and in other advanced cancers in phase I and II clinical trials (Carducci et al, 2006;Faul et al, 2003;Hanauske et al, 2007;Wolff et al, 2011). Ironically, Enzastaurin was developed as a selective inhibitor of PKCb, one of the PKC enzymes down-regulated in melanomas and thus would not be predicted to be effective in melanoma (Faul et al, 2003;Gilhooly et al, 2001;Voris et al, 2010).…”

Section: Protein Kinase C Inhibitors As Therapeutics For Melanomamentioning

confidence: 99%

“…Ironically, Enzastaurin was developed as a selective inhibitor of PKCb, one of the PKC enzymes down-regulated in melanomas and thus would not be predicted to be effective in melanoma (Faul et al, 2003;Gilhooly et al, 2001;Voris et al, 2010). However, multiple mechanisms of action and cellular targets have been described that may account for the anti-melanoma activity of Enzastaurin.…”

Section: Protein Kinase C Inhibitors As Therapeutics For Melanomamentioning

confidence: 99%

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Specifying protein kinase C functions in melanoma

Denning

2012

Pigment Cell Melanoma Res

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SummaryThe protein kinase C (PKC) family of serine/threonine protein kinases is a heterogeneous group of enzymes receiving and integrating signals involved in both normal melanocyte biology and melanoma pathology. Alterations in PKC enzyme expression and activation contribute to the malignant phenotype of melanoma in both oncogenic and tumor suppressive roles. Delineating the diverse and often context‐dependent functions of PKC enzymes in melanocyte/melanoma biology is key to capitalize on these kinases as drug targets. This review summarizes several of the diverse functions of PKC in melanocyte and melanoma biology with a focus on PKC enzyme regulation and function.

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Section: Protein Kinase C Inhibitors As Therapeutics For Melanomamentioning

confidence: 99%

Section: Protein Kinase C Inhibitors As Therapeutics For Melanomamentioning

confidence: 99%

Specifying protein kinase C functions in melanoma

Denning

2012

Pigment Cell Melanoma Res

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“…Enzastaurin, a novel targeted agent, selectively inhibits PKCb by interacting competitively at its ATP-binding site (Faul et al, 2003). Because of its pivotal role in the regulation of tumour-induced angiogenesis, cell cycle progression, tumour cell proliferation, survival, and tumour invasiveness, PKCb is recognised as an important target for cancer treatment (Goekjian and Jirousek, 2001;Liu et al, 2004).…”

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confidence: 99%

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

et al. 2008

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Conventional regimens have limited impact against non-small cell lung cancer (NSCLC). Current research is focusing on multiple pathways as potential targets, and this study investigated molecular mechanisms underlying the combination of the PKCb inhibitor enzastaurin with the multitargeted antifolate pemetrexed in the NSCLC cells SW1573 and A549. Pharmacologic interaction was studied using the combination-index method, while cell cycle, apoptosis induction, VEGF secretion and ERK1/2 and Akt phosphorylation were studied by flow cytometry and ELISAs. Reverse transcription -PCR, western blot and activity assays were performed to assess whether enzastaurin influenced thymidylate synthase (TS) and the expression of multiple targets involved in cancer signaling and cell cycle distribution. Enzastaurin-pemetrexed combination was highly synergistic and significantly increased apoptosis. Enzastaurin reduced both phosphoCdc25C, resulting in G2/M checkpoint abrogation and apoptosis induction in pemetrexed-damaged cells, and GSK3b and Akt phosphorylation, which was additionally reduced by drug combination (À58% in A549). Enzastaurin also significantly reduced pemetrexed-induced upregulation of TS expression, possibly through E2F-1 reduction, whereas the combination decreased TS in situ activity (450% in both cell lines) and VEGF secretion. The effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on the expression of genes involved in pemetrexed activity provide a strong experimental basis to their evaluation as pharmacodynamic markers in clinical trials of enzastaurin-pemetrexed combination in NSCLC patients.

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“…Although this series of compounds didn't make it to clinical testing, it is used experimentally to determine the role of PKC in biological specimens. [50] The structurally related LY-317615 (now known as enzastaurin, Figure 11), first described by Faul et al in 2003, [51] is a PKCβ inhibitor [52] that underwent promising preclinical studies [53] as well as in a Phase I/II clinical trial, [54] but faired disappointingly in Phase III clinical trials. [55,56] The conclusion made was that enzastaurin is "unlikely to be a useful agent as a monotherapy".…”

Section: Pkc Inhibitorsmentioning

confidence: 99%

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Sherer

Snape

2015

European Journal of Medicinal Chemistry

139

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HIGHLIGHTS• Brain cancer mortality rates are much higher than mortality rates for cancers of other sites. •Due to the blood brain barrier, many drugs that work on cancers of other sites do not work on brain cancers • Indoles, carbazoles and indolocarbazoles make good scaffolds for drugs to be built up around due to their rigidity, planarity and ease of synthesis. GRAPHICAL ABSTRACT ACRONYMS/INITIALISMSAML -Acute myeloid leukaemia CK2 -Casein kinase 2 CNS -Central nervous system PARP -Poly ADP ribose polymerase PDGF -Platelet-derived growth factor PKC -Protein kinase C ROS -Reactive oxygen species VEGF -Vascular endothelial growth factor ABSTRACT Tumours of the central nervous system are intrinsically more dangerous than tumours at other sites, and in particular, brain tumours are responsible for 3% of cancer deaths in the UK. Despite this, research into new therapies only receives 1% of national cancer research spend. The most common chemotherapies are temozolomide, procarbazine, carmustine, lomustine and vincristine, but because of the rapid development of chemoresistance, these drugs alone simply aren't sufficient for longterm treatment. Such poor prognosis of brain tumour patients prompted us to research new treatments for malignant glioma, and in doing so, it became apparent that aromatic heterocycles play an important part, especially the indole, carbazole and indolocarbazole scaffolds. This review highlights compounds in development for the treatment of tumours of the central nervous system which are structurally based on the indole, carbazole and indolocarbazole scaffolds, under the expectation that it will highlight new avenues for research for the development of new compounds to treat these devastating neoplasms.

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Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCβ

Cited by 89 publications

References 10 publications

Specifying protein kinase C functions in melanoma

Specifying protein kinase C functions in melanoma

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

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