Blog of Signaling Pathways

Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice

95 views | Mar 08 2020

Llop-Guevara A et al. showed that concurrent JAK + SYK inhibition resulted in higher efficacy than single kinase inhibition and TNF blockade in a chronic and severe arthritis model. Thus, blockade of multiple immune signals with dual JAK + SYK inhibition represents a reasonable therapeutic strategy for RA, in particular in patients with inadequate responses to current treatments. Our data supports the multiplicity of events underlying this heterogeneous and complex disease. [Read the Full Post]

An Ilomastat-CD Eye Drop Formulation to Treat Ocular Scarring

105 views | Mar 06 2020

Mohamed-Ahmed AHA et al. showed that Ilomastat-CD has the potential to be formulated as an eye drop for use as an antifibrotic, which may have implications for the prevention of scarring in many settings, for example glaucoma filtration surgery. [Read the Full Post]

The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy

167 views | Mar 06 2020

Briere D et al. provided evidence that mocetinostat modulates immune-related genes in tumor cells as well as immune cell types in the tumor microenvironment and enhances checkpoint inhibitor therapy. [Read the Full Post]

Precision-cut lung slices from bleomycin treated animals as a model for testing potential therapies for idiopathic pulmonary fibrosis

136 views | Mar 04 2020

Cedilak M et al. suggested that PCLS may be a suitable in vitro model for compound testing during drug development process. [Read the Full Post]

Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder

161 views | Mar 04 2020

De La Garza R 2nd et al. indicated that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder. [Read the Full Post]

Inhibitory effect of 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H - imidazole on HCMV DNA replication and permissive infection

107 views | Mar 03 2020

Johnson RA et al. described FHPI as a novel anti-HCMV compound that inhibits synthesis/activation of cellular and/or viral factors required for initiation of HCMV DNA replication. [Read the Full Post]

The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy

153 views | Mar 03 2020

Marcos-Villar Let al. supported a possible increased vulnerability to infection in MLL-r leukemia patients undergoing pinometostat treatment. Close follow up of infection should be considered in pinometostat therapy to reduce some severe side effects during the treatment. [Read the Full Post]

Phase I Dose-Escalation Study of the pan-HER Inhibitor, PF299804, in Patients With Advanced Malignant Solid Tumors

163 views | Mar 02 2020

Pasi A Jänne et al. showed the MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients. [Read the Full Post]

T-cell death-associated gene 8 accelerates atherosclerosis by promoting vascular smooth muscle cell proliferation and migration

140 views | Mar 02 2020

Chen LD et al. demonstrated that Tdag8 mediated phenotype transformation, proliferation and migration of VSMCs via the cAMP/PKA signaling pathway, thus partially contributing to atherosclerosis. [Read the Full Post]

The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity Against Acute Lymphoblastic Leukemia

88 views | Mar 01 2020

Thomas Vercruysse et al. showed that KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. [Read the Full Post]

URMC-099 Facilitates Amyloid-β Clearance in a Murine Model of Alzheimer's Disease

244 views | Mar 01 2020

Tomomi Kiyota et al. indicated that URMC-099 facilitates Aβ clearance in the brain of APP/PS1 mice. The multifaceted immune modulatory and neuroprotective roles of URMC-099 make it an attractive candidate for ameliorating the course of AD. This is buttressed by removal of pathologic Aβ species and restoration of the brain's microenvironment during disease. [Read the Full Post]

Nuclear-Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

98 views | Feb 28 2020

Dongqing Yan et al. implicated NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis. [Read the Full Post]

An in vitro assay for biomarker discovery and dose prediction applied to ibrutinib plus venetoclax treatment of CLL

72 views | Feb 27 2020

Eide CA et al. suggested that IBR + VEN may represent an effective therapeutic option for patients with AML. [Read the Full Post]

Venetoclax, a BCL-2 Inhibitor, Enhances the Efficacy of Chemotherapeutic Agents in Wild-Type ABCG2-Overexpression-Mediated MDR Cancer Cells

74 views | Feb 27 2020

Wang JQ et al. provided useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice. [Read the Full Post]

Blocking PD1/PDL1 Interactions Together With MLN4924 Therapy Is a Potential Strategy for Glioma Treatment

94 views | Feb 26 2020

Natalia Filippova et al. concluded that i) PDL1 up-regulation in gliomas and the glioma microenvironment is an important chemotherapeutic target; ii) MLN4924 therapy, combined with a blockage of the PD1/PDL1 pathway, should be considered as a potential strategy for glioma treatment. [Read the Full Post]

The Syk Inhibitor Fostamatinib Disodium (R788) Inhibits Tumor Growth in the Eμ- TCL1 Transgenic Mouse Model of CLL by Blocking Antigen-Dependent B-cell Receptor Signaling

138 views | Feb 26 2020

Mirza Suljagic et al. provided further rationale for clinical trials with R788 in CLL and establish the BCR-signaling pathway as an important therapeutic target in this disease. [Read the Full Post]

Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial

193 views | Feb 25 2020

Basset-Séguin N et al. showed the primary analysis of STEVIE demonstrates that vismodegib is tolerable in typical patients in clinical practice; safety profile is consistent with that in previous reports. Long-term exposure was not associated with worsening severity/frequency of TEAEs. Investigator-assessed response rates showed high rate of tumour control. [Read the Full Post]

Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma

216 views | Feb 25 2020

McDermott DF et al. suggested that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade. [Read the Full Post]

Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease

111 views | Feb 23 2020

Michael F Egan et al. indicated that verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. [Read the Full Post]

Crenigacestat, a Selective NOTCH1 Inhibitor, Reduces Intrahepatic Cholangiocarcinoma Progression by Blocking VEGFA/DLL4/MMP13 Axis

349 views | Feb 23 2020

Serena Mancarella et al. developed and validated a new iCCA PDX model to test in vivo the activity of LY3039478, demonstrating its inhibitory role in Notch-dependent angiogenesis. Thus, the present data provide new knowledge on Notch signaling in iCCA, and support the inhibition of the Notch cascade as a promising strategy for the treatment of this disease. [Read the Full Post]