Janus Kinase 2 Inhibitors. Synthesis and Characterization of a Novel Polycyclic Azaindole

Wang, Tiansheng; Duffy, John P.; Wang, Jian; Halas, Summer; Salituro, Francesco G.; Pierce, Albert C.; Zuccola, Harmon; Black, James R.; Hogan, James K.; Jepson, Scott; Shlyakter, Dina; Mahajan, Sudipta; Gu, Yun; Hoock, Thomas; Wood, Mark; Furey, Brinley F.; Frantz, J. Daniel; Dauffenbach, Lisa M.; Germann, Ursula A.; Fan, Bin; Namchuk, Mark; Bennani, Youssef L.; Ledeboer, Mark W.

doi:10.1021/jm901383u

Cited by 38 publications

(20 citation statements)

References 26 publications

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“…The co-crystal structure of JAK2 (PDB ID: 3JY9) was obtained from the RCSB Protein Data Bank (PDB; Berman et al, 2000). The structure was selected based on the following criteria: (1) a crystal structure with a resolution lower than 2.5 Å, (2) a crystal structure containing a potent co-crystal ligand ( K i : 1 nM) (Wang et al, 2009), and (3) a crystal structure with no known mutation. The binding site was prepared using the location of the co-crystallized ligand.…”

Section: Methodsmentioning

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: Methodsmentioning

confidence: 99%

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

et al. 2018

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“…Specifically, compound 15a was shown to form hydrogen bonds with Leu932, Glu930, Glu898, and the backbone NH of Phe995 [17]. In a separate publication, this group described the synthesis of a very similar compound that showed many of the same interactions, with an additional hydrogen bond to the backbone NH of Asp994 [18]. In these studies, the significance of the phenolic hydroxide is highlighted, because it interacts with both Glu898 and Phe995.…”

Section: Pyrimidinesmentioning

confidence: 99%

“…Compound 9 has a phenolic hydroxide component that interacts with both Glu898 and Phe995 [18]. This unique interaction highlights the significance of the location of hydroxyl groups within an inhibitor.…”

Section: Summary Significance and Future Directionsmentioning

confidence: 99%

The Recent Medicinal Chemistry Development of Jak2 Tyrosine Kinase Small Molecule Inhibitors

Baskin

Majumder²,

Sayeski

2010

CMC

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Since the discovery of the Jak2-V617F mutation as the causative agent in a large number of myeloproliferative neoplasms (MPNs), there has been a drive to develop Jak2 specific inhibitors that can be used in therapy for MPN patients and other Jak2-related pathologies. Over the past few years, a number of research groups have sought to develop Jak2 tyrosine kinase inhibitors. These compounds are currently in pre-clinical or clinical trials. Unfortunately, there is still a need for more potent, specific, and orally bioavailable drugs to treat these diseases. Within the past twelve months, a variety of medicinal chemistry techniques have produced several lead compounds that exhibit promising Jak2 inhibitory properties. The majority of these inhibitors target the Jak2 kinase domain in general and the ATP-binding pocket in particular. In this review, we summarize these studies and discuss the structure activity relationship (SAR) properties of several compounds. As we learn more about the key structural components that provide potency and specificity in Jak2 inhibition, we will come closer to finding suitable treatment options for individuals suffering from Jak2-mediated pathologies.

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“…In 2005 it was reported that the occurrence of a single residue mutation in JAK2 was commonly found in patients diagnosed with myeloproliferative disorders [81,82,83,84,85,86]. Blocking the kinase activity of JAK2 by targeting the ATP binding site thus became an attractive therapeutic target [87,88]. Two molecules, the C -3 aryl-7-azaindole derivative 94 (IC 50 JAK2 260 nM) and the aryl purine derivative 95 (IC 50 JAK2 496 nM) emerged as low JAK inhibitors (Scheme 18).…”

Section: Jak2 Inhibitorsmentioning

confidence: 99%

The Azaindole Framework in the Design of Kinase Inhibitors

et al. 2014

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This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors.

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Janus Kinase 2 Inhibitors. Synthesis and Characterization of a Novel Polycyclic Azaindole

Abstract: The synthesis and characterization of a novel polycyclic azaindole based derivative is disclosed, and its binding to JAK2 is described. The compound is further evaluated for its ability to block the EPO/JAK2 signaling cascade in vitro and in vivo.

Cited by 38 publications

References 26 publications

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions

The Recent Medicinal Chemistry Development of Jak2 Tyrosine Kinase Small Molecule Inhibitors

The Azaindole Framework in the Design of Kinase Inhibitors

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