Design and synthesis of an in vivo-efficacious PIM3 kinase inhibitor as a candidate anti-pancreatic cancer agent

Nakano, Hirofumi; Hasegawa, Tsukasa; Saito, Noriko; Furukawa, Kaoru; Mukaida, Naofumi; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo

doi:10.1016/j.bmcl.2015.10.098

Cited by 7 publications

(5 citation statements)

References 30 publications

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“…By combining the heterocyclic moieties at the Brings of 25 and 26, and by introducing an additional methyl group on the methylene bridge between the aurone scaffold and the piperazine group, the authors designed compound 34, which displayed a better anti-PIM3 activity (IC 50 = 2.5 nM) while retaining a good PIM1 inhibitor profile (IC 50 = 1.9 nM) and in vivo efficacy against pancreatic cancers in mice. 52 A further exploration of the impact of a substituent at position 6 of X3 B-ring heterocycle afforded a series of compounds with very high activity against PIM1. Among the studied molecules, 6′-fluoro and 6′-chloro derivatives were found to be particularly promising, both in the 6-methoxy and 6-hydroxy series.…”

Section: Inhibition Of Poly(adp-ribose)polymerases (Parps)mentioning

confidence: 99%

Bioactive Aurones, Indanones, and Other Hemiindigoid Scaffolds: Medicinal Chemistry and Photopharmacology Perspectives

et al. 2022

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Hemiindigoids comprise a range of natural and synthetic scaffolds that share the same aromatic hydrocarbon backbone as well as promising biological and optical properties. The encouraging therapeutic potential of these scaffolds has been unraveled by many studies over the past years and uncovered representants with inspiring pharmacophoric features such as the acetylcholinesterase inhibitor donezepil and the tubulin polymerization inhibitor indanocine. In this review, we summarize the last advances in the medicinal potential of hemiindigoids, with a special attention to molecular design, structure–activity relationship, ligand-target interactions, and mechanistic explanations covering their effects. As their strong fluorogenic potential and photoswitch behavior recently started to be highlighted and explored in biology, giving rise to the development of novel fluorescent probes and photopharmacological agents, we also discuss these properties in a medicinal chemistry perspective.

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Section: Inhibition Of Poly(adp-ribose)polymerases (Parps)mentioning

confidence: 99%

Bioactive Aurones, Indanones, and Other Hemiindigoid Scaffolds: Medicinal Chemistry and Photopharmacology Perspectives

et al. 2022

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“…Nakano et al developed a PIM3 inhibitor (Compound 11) using PIM1's crystal structure as a surrogate to offer a foundation for rational drug design and showed that inhibition of PIM3 kinase activity reduced the proliferation of various pancreatic cancer cell lines. In a mouse xenograft model, compound 11 reduced the development of human pancreatic cancer tumor growth (PCI66) with minimal body weight loss [33]. PIM3 was constitutively expressed in SW480 sarcoma cells, and its inhibition by short hairpin RNA induced apoptosis.…”

Section: Preclinical Studies Of Pim3 In Solid Cancersmentioning

confidence: 99%

PIM3 Kinase: A Promising Novel Target in Solid Cancers

Atalay,

Ozpolat

2024

Cancers

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PIM3 (provirus-integrating Moloney site 3) is a serine/threonine kinase and belongs to the PIM family (PIM1, PIM2, and PIM3). PIM3 is a proto-oncogene that is frequently overexpressed in cancers originating from endoderm-derived tissues, such as the liver, pancreas, colon, stomach, prostate, and breast cancer. PIM3 plays a critical role in activating multiple oncogenic signaling pathways promoting cancer cell proliferation, survival, invasion, tumor growth, metastasis, and progression, as well as chemo- and radiation therapy resistance and immunosuppressive microenvironment. Genetic inhibition of PIM3 expression suppresses in vitro cell proliferation and in vivo tumor growth and metastasis in mice with solid cancers, indicating that PIM3 is a potential therapeutic target. Although several pan-PIM inhibitors entered phase I clinical trials in hematological cancers, there are currently no FDA-approved inhibitors for the treatment of patients. This review provides an overview of recent developments and insights into the role of PIM3 in various cancers and its potential as a novel molecular target for cancer therapy. We also discuss the current status of PIM-targeted therapies in clinical trials.

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“…[81][82][83] The development of 2-alkene derivatives by employing Knoevenagel condensation reaction is discussed. Nagano and co-workers, [84] in the year 2015, prepared a series of 6,7-disubstituted benzofuranones condensed with 1H-pyrazolo [3,4- Compound 44 was displayed significant ADME properties. Therefore, it selectively inhibits PIM2 kinase (IC 50 = 140 nM) (Figure 6).…”

Section: Benzofuran-3-one Derivativesmentioning

confidence: 99%

“…The development of 2‐alkene derivatives by employing Knoevenagel condensation reaction is discussed. Nagano and co‐workers, [84] in the year 2015, prepared a series of 6,7‐disubstituted benzofuranones condensed with 1 H ‐pyrazolo[3,4‐ b ]pyridine aldehydes. All the new derivatives were evaluated for PIM3 kinase and PANC‐1 inhibition.…”

Section: Pharmaceutical Significance Of the Knoevenagel Reactionmentioning

confidence: 99%

Contribution of Knoevenagel Condensation Products toward the Development of Anticancer Agents: An Updated Review

2022

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Knoevenagel condensation is an entrenched, prevailing, prominent arsenal following greener principles in the generation of α, β-unsaturated ketones/carboxylic acids by involving carbonyl functionalities and active methylenes. This reaction has proved to be a major driving force in many multicomponent reactions indicating the prolific utility toward the development of biologically fascinating molecules. This eminent reaction was acclimatised on different pharmacophoric aldehydes (benzimidazole, β-carboline, phenanthrene, indole, imidazothiadiazole, pyrazole etc.) and active methylenes (oxindole, barbituric acid, Meldrum's acid, thiazolidinedione etc.) to generate the library of chemical compounds. Their potential was also explicit to understand the significance of functionalities involved, which thereby evoke further developments in drug discovery. Furthermore, most of these reaction products exhibited remarkable anticancer activity in nanomolar to micromolar ranges by targeting different cancer targets like DNA, microtubules, Topo-I/II, and kinases (PIM, PARP, NMP, p300/CBP) etc. This review underscores the efficiency of the Knoevenagel condensation explored in the past six-year to generate molecules of pharmacological interest, predominantly toward cancer. The present review also provides the aspects of structure-activity relationships, mode of action and docking study with possible interaction with the target protein.

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Design and synthesis of an in vivo-efficacious PIM3 kinase inhibitor as a candidate anti-pancreatic cancer agent

Cited by 7 publications

References 30 publications

Bioactive Aurones, Indanones, and Other Hemiindigoid Scaffolds: Medicinal Chemistry and Photopharmacology Perspectives

Bioactive Aurones, Indanones, and Other Hemiindigoid Scaffolds: Medicinal Chemistry and Photopharmacology Perspectives

PIM3 Kinase: A Promising Novel Target in Solid Cancers

Contribution of Knoevenagel Condensation Products toward the Development of Anticancer Agents: An Updated Review

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