scholarly journals Validation of IMS‐MS as a screening tool to identify type II kinase inhibitors of FGFR1 kinase

2021 ◽  
Author(s):  
Helen S. Beeston ◽  
Tobias Klein ◽  
Richard A. Norman ◽  
Julie A. Tucker ◽  
Malcolm Anderson ◽  
...  
Keyword(s):  
Screening Tool ◽  
Kinase Inhibitors ◽  
Type Ii

1,4-Dihydropyrazolo[4,3-d]imidazole phenyl derivatives: A novel type II Raf kinase inhibitors

2010 ◽  
Vol 20 (12) ◽  
pp. 3805-3808 ◽  
Author(s):  
Hana Yu ◽  
Yunkyung Jung ◽  
Hwan Kim ◽  
Junghun Lee ◽  
Chang-Hyun Oh ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Type Ii ◽  
Raf Kinase

scholarly journals Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

2018 ◽  
Vol 19 (8) ◽  
pp. 2380 ◽  
Author(s):  
Michiel Remmerie ◽  
Veerle Janssens
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Type Ii

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

scholarly journals SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Matthew A. Szaniawski ◽  
Adam M. Spivak ◽  
James E. Cox ◽  
Jonathan L. Catrow ◽  
Timothy Hanley ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Restriction Factor ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Type Iii ◽  
Type Iii Ifn ◽  
Hiv 1

ABSTRACTMacrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA-approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects are exerted primarily through this pathway. Our results demonstrate that SAMHD1 activation, but not transcriptional upregulation or protein induction, is the predominant mechanism of HIV-1 restriction induced by type I, type II, and type III IFN signaling in macrophages. Furthermore, SAMHD1 activation presents a pharmacologically actionable target through which HIV-1 infection can be subverted.IMPORTANCEOur experimental results demonstrate that SAMHD1 dephosphorylation at threonine-592 represents a central mechanism of HIV-1 restriction that is common to the three known families of IFNs. While IFN types I and II were potent inhibitors of HIV-1, type III IFN showed modest to undetectable activity. Regulation of SAMHD1 by IFNs involved changes in phosphorylation status but not in protein levels. Phosphorylation of SAMHD1 in macrophages occurred at least in part via CDK1. Tyrosine kinase inhibitors similarly induced SAMHD1 dephosphorylation, which protects macrophages from HIV-1 in a SAMHD1-dependent manner. SAMHD1 is a critical restriction factor regulating HIV-1 infection of macrophages.

Screening of bipolarity in a depressed population

2011 ◽  
Vol 26 (S2) ◽  
pp. 253-253
Author(s):  
M. Touhami ◽  
F. Ouriaghli ◽  
F. Manoudi ◽  
F. Asri
Keyword(s):  
Major Depressive Episode ◽  
Screening Tool ◽  
Type Ii ◽  
Average Period ◽  
Major Depressive ◽  
History Of ◽  
Proper Diagnosis ◽  
A Prospective Study ◽  
Disorder Type

IntroductionIt's not always evident to diagnose a bipolar disorder.The difficulties of diagnosis have been demonstrated by several studies, some of which have shown that one out of two bipolars consulted at least three health professionals before receiving a proper diagnosis, with an average period of 10 years evolution prior to diagnosis. hypomania is often experienced by patients as a pleasant experience and not a pathological one, rarely have they reported this phenomenon spontaneously. Thus, the diagnosis of hypomania or BP-II disorder is not established in 50% of cases.Aimsto find the prevalence of bipolar disorder type II in a population of depressed people in order to highlight the role of scales in the early identification of this disease often under-diagnosed.Methodsa prospective study of screening for a history of hypomania in a population of patients hospitalized for consultants or major depressive episode or recurrent depressive disorder; over a period of three monthsThe diagnoses of MDE and RDD were prepared according to the DSM-IV.TR.The screening tool is the Hypomania Checklist (HCL French version) which was completed by patients or by the psychiatrist of illiterate patients after its translation into Arabic dialectResults:Sample of 35 patients: 20 women and 15 men, average age: 34 years; Composed of 25 RDD and 10 MED15 patients answered “yes” to 10 or more items of the HCL-20, hypomanic history was confirmed by a clinical interview in 13 of them

A randomized, phase II efficacy assessment of multiple MET kinase inhibitors in metastatic papillary renal carcinoma (PRCC): SWOG S1500.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4599-TPS4599 ◽  
Author(s):  
Sumanta K. Pal ◽  
Catherine M. Tangen ◽  
Ian Murchie Thompson ◽  
Brian M. Shuch ◽  
Naomi B. Haas ◽  
...  
Keyword(s):  
Phase Ii ◽  
Metastatic Disease ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Performance Status ◽  
Progression Free Survival ◽  
Type I ◽  
Type Ii ◽  
Randomized Phase Ii ◽  
Clear Cell Rcc

TPS4599 Background: PRCC constitutes approximately 15% of RCC cases, and no standard of care exists for metastatic disease. Approved VEGF- and mTOR-directed therapies for clear cell RCC in metastatic PRCC (mPRCC) have generally been ineffective. Trials assessing sunitinib and everolimus in non-clear cell RCC show a numerical advantage in progression-free survival (PFS) with sunitinib therapy. Prospective studies evaluating sunitinib in mPRCC show a broad range of efficacy, with PFS ranging from 1.6-6.6 months. Another possible approach to treating mPRCC is to target the MET protooncogene, which is frequently altered across both type I and type II disease. SWOG 1500 is a randomized, phase II study which will compare sunitinib to three MET-directed therapies in pts with mPRCC. Methods: Eligible pts will have PRCC (type I, type II or NOS), Zubrod performance status 0-1, and measurable metastatic disease. Pts may have received up to 1 prior systemic therapy, with the exception of prior VEGF-directed treatments. Treated brain metastases are allowed. Tissue must be available for central pathologic review of papillary subtype. Pts will receive either oral sunitinib, cabozantinib, crizotinib or savolitinib in a 1:1:1:1 randomization, with stratification by (1) prior therapy (0 vs 1) and (2) PRCC subtype (type I vs type II vs NOS). The primary endpoint of the study is to compare PFS with sunitinib to PFS with MET-directed therapies. Secondary endpoints in the study include comparison of response rate, overall survival and safety profile. Translational aims of the study include correlation of clinical outcome with MET mutation, copy number and other markers of MET signaling. Radiographic assessment will be performed every 12 wks. Interim analyses are planned for each arm. A total of 275 pts will be enrolled, with 26 pts registered as of Jan 30, 2017. Clinical trial information: NCT02761057.

Type II Kinase Inhibitors: An Opportunity in Cancer for Rational Design

2013 ◽  
Vol 13 (5) ◽  
pp. 731-747 ◽  
Author(s):  
Javier Blanc ◽  
Raphael Geney ◽  
Christel Menet
Keyword(s):  
Rational Design ◽  
Kinase Inhibitors ◽  
Type Ii
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