Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection

Flanagan, Mark E.; Blumenkopf, Todd A.; Brissette, William H.; Brown, Matthew F.; Casavant, Jeffrey; Shang-Poa, Chang; Doty, Jonathan L.; Elliott, Eileen A.; Fisher, Michael B.; Hines, Michael H.; Kent, Craig R.; Kudlacz, Elizabeth M.; Lillie, Brett M.; Magnuson, Kelly S.; McCurdy, Sandra P.; Munchhof, Michael J.; Perry, Bret D.; Sawyer, Perry S.; Strelevitz, Timothy J.; Subramanyam, Chakrapani; Sun, Jianmin; Whipple, David A.; Changelian, Paul S.

doi:10.1021/jm1004286

Cited by 313 publications

(255 citation statements)

References 36 publications

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“…These findings have potential therapeutic implications, as JAK kinase inhibitors are known to target these alterations. 15,[33][34][35][36][37][38] JAK3 is the most frequently mutated gene (16.1% of T-ALL cases) within the IL7R-JAK signaling pathway. Based on the results described in this article and our previously published work, 15 the transforming capacities of a total of 16 JAK3 mutants have been tested using the Ba/F3 in vitro cell system.…”

Section: Discussionmentioning

confidence: 99%

Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

et al. 2015

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JAK signaling pathway members in 27.7% of T-ALL samples screened; an observation with therapeutic potential. Statistically significant pairwise associations were found between different mutations, indicating the presence of functional interactions among different pathways in T-ALL pathogenesis. Of significance, we found a mutually exclusive relationship between IL7R-JAK mutations and the presence of TAL1/LMO2 rearrangements. We also identified positive correlations among IL7R-JAK mutations and mutations/deletions in PHF6 and members of the PRC2 complex. Our findings begin to unravel the diversity of genetic lesions that are implicated in the development of T-ALL. Methods DNA samplesT-ALL samples from patients (n=155: 111 children, 44 adults) were collected from various institutions (Online Supplementary Table S1). The diagnosis of T-ALL was based on morphology, cytochemistry and immunophenotyping according to World Health Organization criteria. Genomic DNA was isolated from bone marrow (either fixed or fresh bone marrow cells). 5,21,22 To investigate the prognostic relevance of IL7R, JAK1 and JAK3 mutations, Sanger sequencing was used to screen for mutations in these three genes in an independent cohort of 78 T-ALL patients. Those patients were all enrolled into the United Kingdom (UK) Children's Cancer and Leukaemia Group (CCLG) ALL2003 trial. 23This study was approved by the ethics committees of the institutes involved and informed consent was obtained from the participants. Samples and clinical data were stored in accordance with the declaration of Helsinki. Capture designSureDesign software was used to design two slightly different Haloplex capture assays (Table 1). The total amplicon number for design A was 23,127 with a region size of 472.006 kbp and a predicted target coverage of >99%. For design B the total amplicon number was 19,694 with a region size of 418.373 kbp and a predicted target coverage of >99%. For this study, 80 samples were processed with design A and 75 samples with design B. In both assays, the coding exons of selected genes (based on RefSeq, CCDS and VEGA databases) were targeted with an extra ten bases upstream and downstream. Targeted regions comprised the coding sequence of genes that were either recently identified as recurrently mutated in ALL or other hematologic malignancies (known driver genes) or were similar to known oncogenes (candidate driver genes) to be sequenced. 18,19,24,25 For statistical analyses we only considered the 115 genes that were sequenced in both Haloplex designs (Online Supplementary Table S2). Library preparation and sequencing were performed as described in the Online Supplementary Material. Data analysesIn NextGENe software (v2.2.1, Softgenetics, State College, PA, USA), we performed the following steps: (i) the fastQ output file was converted into a FASTA file to eliminate reads that were not "paired" and that did not meet the criteria of the default settings; (ii) reads from the converted unique FASTA file were aligned to the reference genome (...

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Section: Discussionmentioning

confidence: 99%

Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

et al. 2015

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“…Tofacitinib, inhibitor of JAK3 was developed recently [257], but various clinical efficacies have been experienced. A multicentre, double-blind, placebo controlled study with tofacitinib in patients with moderate to severe active CD showed no clinically significant response following 4 weeks of treatment compared with placebo, but in patients with moderate to severe UC it showed improvement in both clinical response and remission rates [258,259].…”

Section: New Avenues Against Pro-inflammatory Cytokines or Downstreammentioning

confidence: 99%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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“…[6 ] The drug inhibits signaling through JAK1 and JAK3 /STATpathway with selectively reduced cellular potency of JAK2. [7]Tofacitinib inhibits signaling by heterodimeric receptors bound among JAK1 and JAK3 with functional selectivity of receptors that signal via JAK2, which blocks signaling for several cytokines and interleukins.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Tofacitinib- A First-In-Class Drug for Rheumatoid Arthritis

Haridoss¹,

Sriram²,

George³

2017

IOSR JDMS

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Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection

Cited by 313 publications

References 36 publications

Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Tofacitinib- A First-In-Class Drug for Rheumatoid Arthritis

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