Structural Basis and Biological Consequences for JNK2/3 Isoform Selective Aminopyrazoles

Park, HaJeung; Iqbal, Saba; Hernandez, Pamela; Mora, Rudy; Zheng, Ke; Feng, Yangbo; LoGrasso, Philip V.

doi:10.1038/srep08047

Cited by 20 publications

(20 citation statements)

References 46 publications

(59 reference statements)

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“…Indeed, perhaps a small amount of JNK inhibition has a large contribution to protecting the mitochondrial membrane potential. 19,26 Similar cell potency was also obtained for other lead compounds in Table 3, such as compounds 12 and 18, indicating this observation was consistent among the class.…”

Section: Acs Medicinal Chemistry Letterssupporting

confidence: 78%

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

Zheng

Park

Iqbal

et al. 2015

ACS Med. Chem. Lett.

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A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure−activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC 50 = 15 nM), had high selectivity against p38 (IC 50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 Å. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition. A s a member of the mitogen-activated protein kinase (MAPK) family, the c-Jun N-terminal kinases (JNKs) are activated (dual phosphorylation on threonine and tyrosine) via an upstream kinase signaling cascade initiated by environmental stress and culminate in effects on both nuclear and mitochondrial function. 1−3 It is well-known that there are three human JNK isoforms, JNK1, JNK2, and JNK3. 4 JNK1 and JNK2 are ubiquitously expressed in a variety of human tissues. 2,5 Recent studies showed that JNK1 and JNK2 play an important role in the development of diabetes, obesity, arthritis, cancer, and heart disease. JNK1 seems to be involved in the development of obesity induced insulin resistance, which implies inhibition of JNK1 might be an effective way of treating type-2 diabetes. 6,7 JNK2 has been implicated to play an important role in many autoimmune disorders such as rheumatoid arthritis, asthma, and cancer, as well as in a broad range of diseases with an inflammatory component. 5,8 JNK3 is primarily expressed in the central nervous system (CNS) and plays an important role in Alzheimer's disease, 9 Parkinson's disease, and stroke. 3,10,11 Therefore, JNK inhibitors may have implications in many therapeutic areas, and development of JNK inhibitors as therapeutic agents has gained considerable interest over the past few years. 12−17 Given the significant amount of evidence supporting the role of JNK3 in neurodegenerative disorders, our interest is in discovering potent, selective JNK3 inhibitors with good in vivo pharmacokinetics (PK) profiles as potential therapeutics for CNS disease. 3,10,11,18−20 The pyridopyrimidinone scaffold based compound 1 (Figure 1) was identified in our preliminary medicinal chemistry efforts as an ATP competitive pan-JNK inhibitor with an IC 50 of 58 nM against JNK3 and 18 nM over both JNK1 and JNK2. This scaffold (pyridopyrimidinone) has long been shown to be good for kinase inhibition. 21 While genetic evidence suggests that JNK1 inhibition is not required for efficacy in many CNS applications, the...

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Section: Acs Medicinal Chemistry Letterssupporting

confidence: 78%

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

Zheng

Park

Iqbal

et al. 2015

ACS Med. Chem. Lett.

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“…For example, selective JNK1/3 inhibitors may have clinical benefit in treating neurodegenerative disorders [24]. However, it has been difficult to design selective JNK inhibitors because of the high sequence identity among JNK isoforms (from 73 to 75%) and, specifically, sequence identity of their ATP binding pockets (close to 98%) [25]. Recently, JNK2/3 inhibitors with an aminopyrazole scaffold that have >30-fold selectivity over JNK1 were identified [25].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors

Schepetkin

Khlebnikov

Potapov

et al. 2019

European Journal of Medicinal Chemistry

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c-Jun N-terminal kinases (JNKs) play a central role in many physiologic and pathologic processes. We synthesized novel 11H-indeno[1,2-b]quinoxalin-11-one oxime analogs and tryptanthrin-6-oxime (indolo(2,1-b)quinazoline-6,12-dion-6-oxime) and evaluated their effects on JNK activity. Several compounds exhibited sub-micromolar JNK binding affinity and were selective for JNK1/JNK3 versus JNK2.The most potent compounds were 10c (11H-indeno[1,2b]quinoxalin-11-one O-(O-ethylcarboxymethyl) oxime) and tryptanthrin-6-oxime, which had dissociation constants (Kd) for JNK1 and JNK3 of 22 and 76 nM and 150 and 275 nM, respectively. Molecular modeling suggested a mode of binding interaction at the JNK catalytic site and that the selected oxime derivatives were potentially competitive JNK inhibitors. JNK binding activity of the compounds correlated with their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation in human monocytic THP-1Blue cells and interleukin-6 (IL-6) production by human MonoMac-6 cells. Thus, oximes with indenoquinoxaline and tryptanthrin nuclei can serve as specific smallmolecule modulators for mechanistic studies of JNK, as well as potential leads for the development of anti-inflammatory drugs.

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“…The presence of Leu144 provides the proper accommodation of the naphthalene ring into the selectivity binding pocket, which is not possible in other MAPKs. Another study confirmed this finding when it suggested that Leu144 located within the hydrophobic pocket of JNK3 was responsible for the selectivity [ 144 ]. On the other hand, the selectivity of JNK3 over JNK2 is explained by the presence of isoleucine and methionine residues (Ile92 and Met115) in the JNK3 isoform, while the JNK2 isoform presents valine and leucine residues in the same position (Val54 and Leu77).…”

Section: General Aspects Of Mitogen-activated Protein Kinases (Mapmentioning

confidence: 77%

c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases

Rehfeldt

Majolo

Goettert

et al. 2020

IJMS

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Alzheimer’s Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review.

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Structural Basis and Biological Consequences for JNK2/3 Isoform Selective Aminopyrazoles

Cited by 20 publications

References 46 publications

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors

c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases

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