Identification of 8‐Hydroxyquinoline Derivatives Active Against Somatic V658F Mutant JAK1‐Dependent Cells

Kingsford-Adaboh, Robert; Bajusz, Dávid; Baskin, Rebekah; Tóth, Katalin; Monostory, Katalin; Sayeski, Peter P.; Keserü, György M.

doi:10.1002/ardp.201600246

Cited by 6 publications

(11 citation statements)

References 34 publications

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“…In this study, we performed a structure-based virtual screening of the NCI database to identify novel and specific JAK2 inhibitors. While in silico screening for JAK1 or JAK2 inhibitors using the NCI database have been carried out previously (Kiss et al, 2009, 2016), we devised a new strategy to increase the hit rates for potential inhibitors. First, to increase our hit rate, we identified pharmacological interactions by docking known JAK2 inhibitors.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

et al. 2018

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“…Analogues containing these moieties showed the best outcomes regarding somatic V658F mutant JAK1-dependent cells, combining the lower IC 50 with the minimized liver toxicity. [53] 8-Hydroxyquioline analogues target V658F-mutated JAK1 with potency and could represent an interesting and pioneering target therapy, especially for acute lymphoblastic leukemia, where the cells demonstrate expression of the mutation on V658F. This target therapy consists of a very relevant strategy to obtain selectivity, a prioritized aspect considering that adverse effects are one of the main problems of conventional antileukemia treatment.…”

Section: Inhibition Of Janus Kinase (Jak1)mentioning

confidence: 99%

“…This target therapy consists of a very relevant strategy to obtain selectivity, a prioritized aspect considering that adverse effects are one of the main problems of conventional antileukemia treatment. [53]…”

Section: Inhibition Of Janus Kinase (Jak1)mentioning

confidence: 99%

“…JAK inhibitors are a versatile set of small molecules used in the management of inflammatory conditions, such as autoimmune disorders and cancer [52] . Somatic gain‐of‐function mutations, such as the V658F mutation in JAK1, result in its uninterrupted activation (without cytokines or binding of other molecules), which leads to the antiapoptotic effect observed in leukemia progression [53] . This genetic alteration in V658F of JAK1 is identified mostly in acute lymphoblastic leukemia, but also in acute myeloid leukemia.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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8‐Hydroxyquinoline, Derivatives and Metal‐Complexes: A Review of Antileukemia Activities

Gasparin

Pilger

2023

ChemistrySelect

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8‐Hydroxyquinoline and its derivatives consist of a group of metal‐binding ligands capable of reaching complexes that present several biological activities. In the present study, we collate and discuss data regarding the antileukemia activities of 8‐hydroxyquinoline (8HQ) compounds to provide an overview of their mechanisms of actions, and a compilation of cytotoxicity data against diverse leukemia cell lines. The pharmacological activities of this class of agents are associated primarily with their ability to coordinate metals and interact with multiple biological targets. We found consistent evidence that 8HQ exerts promising proapoptotic features through its direct interaction with deoxyribonucleic acid (DNA) and inhibition of multiple targets, such as the proteasome, nuclear factor kappa B (NF‐κB), histone deacetylase (HDAC), bromodomain and extra terminal (BET) proteins and janus kinases (JAKs), in addition to inducing autophagy associated cell death. Thus, we provide substantial evidence for the repositioning potential of the 8HQ class for the treatment of leukemia, a hematological malignancy for which urgent advances in therapeutic approaches are needed to overcome conventional therapy limitations.

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“…JAK3 is a member of the JAK family of non‐receptor tyrosine kinases, which contains JAK1, JAK2, and TYK2 . JAK3, expressing in hematopoietic tissues, is solely activated by type I cytokine receptors featuring a common γ‐chain (γ c ) subunit that was activated by IL‐2, IL‐4, IL‐7, IL‐9, IL‐15, and IL‐21, then leads to the phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins, and regulates target gene expression that governs cell development, survival, differentiation, and proliferation in immune system .…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis

Pei

Lan

et al. 2017

Archiv der Pharmazie

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Selective inhibition of Janus kinase 3 (JAK3) has been identified as an important strategy for the treatment of autoimmune disorders. Based on the unique cysteine 909 residue (Cys909) of JAK3 at the gatekeeper position, we have developed a new irreversible covalent inhibitor, III-4, which is highly potent and selective in targeting JAK3. Importantly, III-4 selectively inhibited JAK3 (IC = 57 ± 1.21 nM) over other JAKs (IC > 10 µM) and Cys909 kinome members (IC > 1 µM). A cellular selectivity study also confirmed that III-4 preferentially inhibited JAK3 over JAK1 in JAK/STAT signaling. Moreover, the fact that III-4 covalently modified the Cys909 residue in JAK3 was clearly validated by mass spectrometry and covalent docking analysis. Based on the favorable target profiles, the pharmacokinetic properties and its low toxicity, III-4 exhibited better efficacy than tofacitinib in impeding disease progression in CIA mice, without any significant adverse effects. Taken together, III-4 is a potent, selective, and durable inhibitor of JAK3 and has the potential for the treatment of inflammatory disorders and autoimmune diseases, such as rheumatoid arthritis.

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Identification of 8‐Hydroxyquinoline Derivatives Active Against Somatic V658F Mutant JAK1‐Dependent Cells

Cited by 6 publications

References 34 publications

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

8‐Hydroxyquinoline, Derivatives and Metal‐Complexes: A Review of Antileukemia Activities

Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis

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