Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide c-Jun NH<sub>2</sub>-Terminal Kinase Inhibitors

Zhao, Hongyu; Serby, Michael D.; Xin, Zhili; Szczepankiewicz, Bruce G.; Liu, Mei; Kosogof, Christi; Liu, Bo; Nelson, Lawrence J.; Johnson, Eric F.; Wang, Sanyi; Pederson, Terry M.; Gum, Rebecca J.; Clampit, Jill E.; Haasch, Deanna L.; Abad‐Zapatero, Celerino; Fry, Elizabeth H.; Rondinone, Cristina M.; Trevillyan, James M.; Sham, Hing L.; Liu, Gang

doi:10.1021/jm060465l

Cited by 73 publications

(62 citation statements)

References 30 publications

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“…In contrast to p38, there have been fewer reports for selective JNK inhibitors, and the clinical development of JNK inhibitors also lags that of p38. Despite the paucity of highly selective JNK inhibitors that have advanced to clinical development, numerous recent reports have begun to emerge that show compounds from various structural classes (benzothiazole pyrimidines, aminopyridines, benzothien-2-yl amides, aminopyrimidines, and quinolines) having selectivity for JNK over p38 (5,15,17,(22)(23)(24). The well described toxicity of p38 inhibition (7) necessitates this desired selectivity in any JNK inhibitor program.…”

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confidence: 99%

“…p38 especially has garnered considerable interest, particularly for the treatment of rheumatoid arthritis and Crohn disease, and numerous compounds have entered clinical trials for these indications (7)(8)(9)(10)(11). Because most of the p38 inhibitors are competitive versus ATP (12)(13)(14)(15)(16)(17), and there are 518 kinases in the genome, it was crucial to develop compounds that are selective against a broad panel of kinases so that compounds could be advanced to clinical development. The molecular basis that gives rise to selective p38 inhibitors from numerous structural classes has been reported (18 -20) and is centered on amino acid differences at the so-called "gatekeeper" Thr-106 residue in p38 (Met in all of the JNK isoforms and Gln in extracellular regulated kinase, the other mitogenactivated protein kinase family member).…”

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confidence: 99%

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Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Kamenecka

Habel

Duckett

et al. 2009

Journal of Biological Chemistry

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c-Jun N-terminal kinase 3␣1 (JNK3␣1) is a mitogen-activated protein kinase family member expressed primarily in the brain that phosphorylates protein transcription factors, including c-Jun and activating transcription factor-2 (ATF-2) upon activation by a variety of stress-based stimuli. In this study, we set out to design JNK3-selective inhibitors that had >1000-fold selectivity over p38, another closely related mitogen-activated protein kinase family member. To do this we employed traditional medicinal chemistry principles coupled with structurebased drug design. Inhibitors from the aminopyrazole class, such as SR-3576, were found to be very potent JNK3 inhibitors (IC 50 ‫؍‬ 7 nM) with >2800-fold selectivity over p38 (p38 IC 50 > 20 M) and had cell-based potency of ϳ1 M. In contrast, indazole-based inhibitors exemplified by SR-3737 were potent inhibitors of both JNK3 (IC 50 ‫؍‬ 12 nM) and p38 (IC 50 ‫؍‬ 3 nM). These selectivity differences between the indazole class and the aminopyrazole class came despite nearly identical binding (root mean square deviation ‫؍‬ 0.33 Å ) of these two compound classes to JNK3. The structural features within the compounds giving rise to the selectivity in the aminopyrazole class include the highly planar nature of the pyrazole, N-linked phenyl structures, which better occupied the smaller active site of JNK3 compared with the larger active site of p38.Because the initial reports on the discovery of p38 (1) and c-Jun N-terminal kinase (JNK) 2 (2-6) these mitogen-activated protein kinase family members have generated great interest as drug targets. p38 especially has garnered considerable interest, particularly for the treatment of rheumatoid arthritis and Crohn disease, and numerous compounds have entered clinical trials for these indications (7-11). Because most of the p38 inhibitors are competitive versus ATP (12-17), and there are 518 kinases in the genome, it was crucial to develop compounds that are selective against a broad panel of kinases so that compounds could be advanced to clinical development. The molecular basis that gives rise to selective p38 inhibitors from numerous structural classes has been reported (18 -20) and is centered on amino acid differences at the so-called "gatekeeper" Thr-106 residue in p38 (Met in all of the JNK isoforms and Gln in extracellular regulated kinase, the other mitogenactivated protein kinase family member). Many compounds have been synthesized that take advantage of this deeper hydrophobic pocket in p38, compared with JNK3, and the structures of the compounds have included trifluoromethyl and other large moieties, which all contribute to p38 selectivity (21). In contrast to p38, there have been fewer reports for selective JNK inhibitors, and the clinical development of JNK inhibitors also lags that of p38. Despite the paucity of highly selective JNK inhibitors that have advanced to clinical development, numerous recent reports have begun to emerge that show compounds from various structural classes (benzothiazole pyrimidines, aminopyr...

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confidence: 99%

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confidence: 99%

Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Kamenecka

Habel

Duckett

et al. 2009

Journal of Biological Chemistry

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“…3,[21][22][23][24] Overall structure of JNK1 and the superimposed model of five JNK1 inhibitors are represented in Figure 1. JNK1 inhibitors formed commonly two hydrogen bonds with backbone amide proton of M111 and backbone carbonyl oxygen of E109, respectively.…”

Section: Resultsmentioning

confidence: 99%

Docking Study of Flavonols and Human c-Jun N-terminal Kinase 1

Lee¹,

Jeong²,

Heo³

et al. 2010

Bulletin of the Korean Chemical Society

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c-Jun N-terminal kinase 1 (JNK1) is involved in apoptosis, cell differentiation and proliferation. It has been reported that a flavonol, quercetin, induces cell apoptosis and JNK inhibition. In order to understand the interactions of quercetin and JNK1, we performed receptor-oriented pharmacophore based in silico screening and determined a binding model of human JNK1 and quercetin at the ATP binding site of JNK1. 5-OH of A-ring and carbonyl oxygen of C-ring of quercetin participated in hydrogen bonding interactions with backbone of E109 and M111. Additionally, 3'-OH of quercetin formed a hydrogen bond with backbone of I32. One hydrophobic interaction is related on the binding of quercetin to JNK1 with I32, N114, and V158. Based on this model, we conducted a docking study with other 8 flavonols to find possible flavonoids inhibitors of JNK1. We proposed that one flavonols, rhamnetin, can be a potent inhibitor of JNK and 5-OH of A-ring and 3'-OH of B-ring of flavonols are the essential features for JNK1 inhibition.

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“…Docking study was carried out using the enzyme parameters obtained from the crystallographic structure of the complex between JNK1 with the co-crystallized pyridine carboxamide ( Figure 5) (PDB ID: 2H96) 42 . The docking simulation for the ligand was carried out using molecular operating environment (MOE) software supplied by the Chemical Computing Group, Inc., Montréal, QC 43 .…”

Section: Docking Studymentioning

confidence: 99%

Novel thiosemicarbazides induced apoptosis in human MCF-7 breast cancer cells via JNK signaling

Malki

Elbayaa

Ashour

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this study, novel thiosemicarbazides and 1,3,4-oxadiazoles were synthesized and evaluated for their anticancer effects on human MCF-7 breast cancer cell lines. Among the synthesized derivatives studied, compound 2-(3-(4-chlorophenyl)-3-hydroxybutanoyl)-N-phenylhydrazinecarbothioamide 4c showed the highest cytotoxicity against MCF-7 breast cancer cells as it reduced cell viability to approximately 15% compared to approximately 25% in normal breast epithelial cells. Therefore, we focused on 4c for further investigations. Our data showed that 4c induced apoptosis in MCF-7 cells which was further confirmed by TUNEL assay. Western blotting analysis showed that compound 4c up-regulated the pro-survival proteins Bax, Bad and ERK1/2, while it down-regulated anti-apoptotic proteins Bcl-2, Akt and STAT-3. Additionally, 4c induced phosphorylation of SAPK/JNK in MCF-7 cells. Pretreatment of MCF-7 cells with 10 mM of JNK inhibitor significantly reduced 4c-induced apoptosis. Molecular docking results suggested that compound 4c showed a binding pattern close to the pattern observed in the structure of the lead fragment bound to JNK1. Collectively, the data of current study suggested that the thiosemicarbazide 4c might trigger apoptosis in human MCF-7 cells by targeting JNK signaling.

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Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide c-Jun NH₂-Terminal Kinase Inhibitors

Cited by 73 publications

References 30 publications

Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Docking Study of Flavonols and Human c-Jun N-terminal Kinase 1

Novel thiosemicarbazides induced apoptosis in human MCF-7 breast cancer cells via JNK signaling

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Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide c-Jun NH2-Terminal Kinase Inhibitors

Cited by 73 publications

References 30 publications

Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38

Docking Study of Flavonols and Human c-Jun N-terminal Kinase 1

Novel thiosemicarbazides induced apoptosis in human MCF-7 breast cancer cells via JNK signaling

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Product

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Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide c-Jun NH₂-Terminal Kinase Inhibitors