Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases

Casuscelli, F.; Ardini, Elena; Avanzi, Nilla; Casale, Elena; Cervi, Giovanni; D'Anello, Matteo; Donati, Daniele; Faiardi, Daniela; Ferguson, R. D.; Fogliatto, Gianpaolo; Galvani, Arturo; Marsiglio, Aurelio; Mirizzi, Danilo; Montemartini, Marisa; Orrenius, Christian; Papeo, Gianluca; Piutti, Claudia; Salom, Barbara; Felder, E.

doi:10.1016/j.bmc.2013.09.054

Cited by 31 publications

(25 citation statements)

References 59 publications

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“…It thus represents an encouraging target for anticancer drug discovery. The novel PIM1 inhibitor NMS-P645 has been recently described and shows strong specificity for PIM family members against a panel of kinases representing all the human protein kinase families 21. We here demonstrate the activity of this compound in PCa cells, showing its growth inhibition effects in combination with the PI3K inhibitor GDC-0941.…”

Section: Discussionmentioning

confidence: 61%

“…The PI3K/AKT pathway is commonly hyper-activated in prostate cancer, but the therapeutic efficacy of its inhibition is limited by the presence of compensatory pathways mediated, at least in part, by PIM1 activity 20. Here we show the biological activity of the newly described PIM1 inhibitor NMS-P645 21 in prostate cancer cell lines, demonstrating its anti-proliferative role when used in combination with the PI3K inhibitor GDC-0941 22.…”

Section: Introductionmentioning

confidence: 73%

“…NMS-P645 was synthesized by Nerviano Medical Sciences as described 21. GDC-0941 and vandetanib were purchased from Selleck Chemicals.…”

Section: Methodsmentioning

confidence: 99%

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The Novel PIM1 Inhibitor NMS-P645 Reverses PIM1-Dependent Effects on TMPRSS2/ERG Positive Prostate Cancer Cells And Shows Anti-Proliferative Activity in Combination with PI3K Inhibition

Mologni¹,

Magistroni²,

Casuscelli³

et al. 2017

J. Cancer

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PIM1 is over-expressed in multiple tumors, including prostate cancer (PCa). PIM1 upregulation is mediated by direct binding of the ERG transcription factor to its promoter. About 50% of PCa cases are characterized by the presence of the TMPRSS2/ERG fusion, leading to ERG over-expression and thus to PIM1 transcriptional activation. PIM kinases are considered as weak oncogenes, but when combined with additional genetic alterations can induce strong transforming effects. Here we show anti-proliferative activity of the newly described PIM1 inhibitor NMS-P645 in combination with the PI3K inhibitor GDC-0941 in TMPRSS2/ERG positive and negative PCa cells. Treatment with NMS-P645 alone can reverse PIM1-mediated pro-survival signals in prostate cells, such as activation of STAT3 through Tyr705 phosphorylation and resistance to taxane-based treatments, but does not exert a strong anti-tumoral effect. However, the simultaneous treatment with NMS-P645 and GDC-0941 induces a significant anti-proliferative response in PCa cells. These results support the use of combination strategies with PIM and PI3K inhibitors as effective treatment for PCa cases.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 73%

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The Novel PIM1 Inhibitor NMS-P645 Reverses PIM1-Dependent Effects on TMPRSS2/ERG Positive Prostate Cancer Cells And Shows Anti-Proliferative Activity in Combination with PI3K Inhibition

Mologni¹,

Magistroni²,

Casuscelli³

et al. 2017

J. Cancer

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“…For example, Pim-1 is identified to have remarkable specificity for a subset of 3,6-disubstituted imidazo[1,2-b]pyridazine and 3,5-disubstituted pyrazolo[1,5-a]pyrimidine scaffolds [103,108,119]. 3,4-Dihydropyrrolo[1,2-a] pyrazin-1(2H)-one derivative 4 ( Figure 4B & Table 1) is a modest active Pim-1 inhibitor [120], but it presents an interesting binding mode. It does not form hydrogen bond with the hinge residues.…”

Section: Design Of Pim Inhibitorsmentioning

confidence: 98%

Targeting Pim Kinases for Cancer Treatment: Opportunities and Challenges

Kumarasiri

Adams

et al. 2015

Future Med. Chem.

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Pim oncogenes are highly expressed in many types of hematological and solid cancers. Pim kinases regulate the network of signaling pathways that are critical for tumorigenesis and development, making Pim kinases the attractive drug targets. Currently, two approaches have been employed in designing Pim kinase inhibitors: ATP-mimetics and non-ATP mimetics; but all target the ATP-binding pocket and are ATP-competitive. In this review, we summarize the current progress in understanding the Pim-related structure and biology, and provide insights into the binding modes of some prototypical Pim-1 inhibitors. The challenges as well as opportunities are highlighted for development of Pim kinase inhibitors as potential anticancer agents.

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“…Pyrrolopyrazines 1 have also been described as melanin-concentrating hormone (MCH-R1) antagonists of interest in antiobesity therapy [25]. Other notable bioactive derivatives are the HIV-1 integrase compounds 2 [26], the potent and noncompetitive mGluR1 antagonists 3 [27], the kinase inhibitors 4 [28] and 5 [29] and the immunosuppressive response indoleamine-2,3-dioxygenase 1 (IDO-1) inhibitors 6 [30] (Figure 2). In view of these bioactivities, there has been a keen interest in synthetic analogs, and pyrrolopyrazine is now recognized as a privileged scaffold.…”

Section: Introductionmentioning

confidence: 99%

A Review of the Synthetic Strategies toward Dihydropyrrolo[1,2-a]Pyrazinones

et al. 2021

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Dihydropyrrolo[1,2-a]pyrazinone rings are a class of heterocycles present in a wide range of bioactive natural products and analogues thereof. As a direct result of their bioactivity, the synthesis of this privileged class of compounds has been extensively studied. This review provides an overview of these synthetic pathways. The literature is covered up until 2020 and is organized according to the specific strategies used to construct the scaffold: fusing a pyrazinone to an existing pyrrole, employing a pyrazinone-first strategy, an array of multicomponent reactions and some miscellaneous reactions.

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Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases

Cited by 31 publications

References 59 publications

The Novel PIM1 Inhibitor NMS-P645 Reverses PIM1-Dependent Effects on TMPRSS2/ERG Positive Prostate Cancer Cells And Shows Anti-Proliferative Activity in Combination with PI3K Inhibition

The Novel PIM1 Inhibitor NMS-P645 Reverses PIM1-Dependent Effects on TMPRSS2/ERG Positive Prostate Cancer Cells And Shows Anti-Proliferative Activity in Combination with PI3K Inhibition

Targeting Pim Kinases for Cancer Treatment: Opportunities and Challenges

A Review of the Synthetic Strategies toward Dihydropyrrolo[1,2-a]Pyrazinones

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