Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors

Simov, Vladimir; Deshmukh, Sujal V.; Dinsmore, Christopher J.; Elwood, Fiona; Fernández, Rafael; Garcia, Yudith; Gibeau, Craig; Günaydın, Hakan; Jung, Joon; Katz, Jason D.; Kraybill, Brian; Lapointe, Blair T.; Patel, Sangita; Siu, Tony; Su, Hua; Young, Jonathan R.

doi:10.1016/j.bmcl.2016.02.035

Cited by 20 publications

(9 citation statements)

References 19 publications

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“…As a result, we compared the structure of inhibitor NSC13626 with known JAK2 inhibitors obtained from BindingDB (Figure 6A). We focused three set, each with a scaffold core with modifications (Ledeboer et al, 2009; Lim et al, 2011; Simov et al, 2016). These three sets contain the most JAK2 inhibitors from BindingDB.…”

Section: Resultsmentioning

confidence: 99%

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

et al. 2018

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The JAK2/STAT signaling pathway mediates cytokine receptor signals that are involved in cell growth, survival and homeostasis. JAK2 is a member of the Janus kinase (JAK) family and aberrant JAK2/STAT is involved with various diseases, making the pathway a therapeutic target. The similarity between the ATP binding site of protein kinases has made development of specific inhibitors difficult. Current JAK2 inhibitors are not selective and produce unwanted side effects. It is thought that increasing selectivity of kinase inhibitors may reduce the side effects seen with current treatment options. Thus, there is a great need for a selective JAK inhibitor. In this study, we identified a JAK2 specific inhibitor. We first identified key pharmacological interactions in the JAK2 binding site by analyzing known JAK2 inhibitors. Then, we performed structure-based virtual screening and filtered compounds based on their pharmacological interactions and identified compound NSC13626 as a potential JAK2 inhibitor. Results of enzymatic assays revealed that against a panel of kinases, compound NSC13626 is a JAK2 inhibitor and has high selectivity toward the JAK2 and JAK3 isozymes. Our cellular assays revealed that compound NSC13626 inhibits colorectal cancer cell (CRC) growth by downregulating phosphorylation of STAT3 and arresting the cell cycle in the S phase. Thus, we believe that compound NSC13626 has potential to be further optimized as a selective JAK2 drug.

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Section: Resultsmentioning

confidence: 99%

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

et al. 2018

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“…Furthermore, poly(GR) and poly(PR) also caused a toxic translational arrest that can be restored by exogenous expression of eIF1A (Moens et al, 2019 ). In a motor neuron cell line, Kanekura et al ( 2016 ) demonstrated that C9-arginine-rich DPRs impaired protein translation by sequestering translation factors (eIF3A, eEF1A; Simov et al, 2016 ). Moreover, in NSC34 cells, Suzuki et al ( 2018 ) also indicated that C9-poly(PR) disrupted translational machinery by reducing ribosomal RNA expression levels.…”

Section: Impaired Translational Control Resulting From Energy Dysfunction In Neurodegenerative Diseasesmentioning

confidence: 99%

Contribution of Energy Dysfunction to Impaired Protein Translation in Neurodegenerative Diseases

Liu

Chern

2021

Front. Cell. Neurosci.

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Impaired energy homeostasis and aberrant translational control have independently been implicated in the pathogenesis of neurodegenerative diseases. AMP kinase (AMPK), regulated by the ratio of cellular AMP and ATP, is a major gatekeeper for cellular energy homeostasis. Abnormal regulation of AMPK has been reported in several neurodegenerative diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Most importantly, AMPK activation is known to suppress the translational machinery by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1), activating translational regulators, and phosphorylating nuclear transporter factors. In this review, we describe recent findings on the emerging role of protein translation impairment caused by energy dysregulation in neurodegenerative diseases.

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“…The peculiarity of this work consisted in exploiting the available crystallographic information to develop JAK1-selective and higher affinity inhibitors. The outcome not only afforded a hit compound with high specificity towards JAK1, but also highlighted the importance of targeting key residues within the binding site of JAK1 (Arg879 and Glu966) [ 135 ].…”

Section: Enhancing Jakis Discovery Through Structure-based Drug Dementioning

confidence: 99%

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

et al. 2020

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The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

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Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors

Cited by 20 publications

References 19 publications

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

Contribution of Energy Dysfunction to Impaired Protein Translation in Neurodegenerative Diseases

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

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