An open-label, dose escalating Phase Ib study for the assessment of safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple intravenous doses of GLPG0187 in subjects with solid tumors. - Phase Ib study with GLPG0187 in subjects with solid tumors.

Start Date22 Mar 2011

Sponsor / Collaborator-

NCT01313598

/ CompletedPhase 1

An Open-label, Dose Escalating Phase Ib Study for the Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Intravenous Doses of GLPG0187 in Subjects With Solid Tumors

The purpose of the study is to determine the safety and tolerability of GLPG0187 administered through continuous intravenous infusion and to explore its preliminary clinical efficacy in patients with solid tumors.

Start Date01 Mar 2011

Sponsor / Collaborator

Galapagos NV

NCT00928343

/ CompletedPhase 1

Double Blind Placebo Controlled Dose Ranging Study for the Assessment of Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of Single Ascending Subcutaneous and Oral Doses of GLPG0187 in Healthy Subjects.

The purpose of the study is to evaluate the safety and tolerability of single ascending (SAD) subcutaneous and single oral dose of GLPG0187 compared to placebo.
Also, pharmacokinetics (PK) and pharmacodynamics (PD) of GLPG0187 after single subcutaneous and oral administration will be evaluated, and, if applicable, the maximum tolerated dose determined.

Start Date01 Jun 2009

Sponsor / Collaborator

Galapagos NV

100 Clinical Results associated with GLPG-0187

100 Translational Medicine associated with GLPG-0187

100 Patents (Medical) associated with GLPG-0187

Literatures (Medical) associated with GLPG-0187

01 Feb 2024·Journal of Biological Chemistry

IraM remodels the RssB segmented helical linker to stabilize σs against degradation by ClpXP

Article

Author: Srirangam, Srinivas ; Deaconescu, Alexandra M ; Brugger, Christiane

Upon Mg²⁺ starvation, a condition often associated with virulence, enterobacteria inhibit the ClpXP-dependent proteolysis of the master transcriptional regulator, σ^s, via IraM, a poorly understood antiadaptor that prevents RssB-dependent loading of σ^s onto ClpXP. This inhibition results in σ^s accumulation and expression of stress resistance genes. Here, we report on the structural analysis of RssB bound to IraM, which reveals that IraM induces two folding transitions within RssB, amplified via a segmented helical linker. These conformational changes result in an open, yet inhibited RssB structure in which IraM associates with both the C-terminal and N-terminal domains of RssB and prevents binding of σ^s to the 4-5-5 face of the N-terminal receiver domain. This work highlights the remarkable structural plasticity of RssB and reveals how a stress-specific RssB antagonist modulates a core stress response pathway that could be leveraged to control biofilm formation, virulence, and the development of antibiotic resistance.

01 Jul 2023·Arteriosclerosis, Thrombosis, and Vascular Biology

Lineage-Specific Induced Pluripotent Stem Cell–Derived Smooth Muscle Cell Modeling Predicts Integrin Alpha-V Antagonism Reduces Aortic Root Aneurysm Formation in Marfan Syndrome Mice

Article

Author: Mitchel, Olivia ; Nakamura, Ken ; Leipzig, Matthew ; Uchida, Tetsuro ; Dalal, Alex R ; Fischbein, Michael P ; Casey, Kerriann M ; Gilles, Casey ; Yokoyama, Nobu ; Hiesinger, William ; Pedroza, Albert J ; Masoudian, Bahar ; Kusadokoro, Sho

Background:The role of increased smooth muscle cell (SMC) integrin αv signaling in Marfan syndrome (MFS) aortic aneurysm remains unclear. Herein, we examine the mechanism and potential efficacy of integrin αv blockade as a therapeutic strategy to reduce aneurysm progression in MFS.Methods: Induced pluripotent stem cells (iPSCs) were differentiated into aortic SMCs of the second heart field (SHF) and neural crest (NC) lineages, enabling in vitro modeling of MFS thoracic aortic aneurysms. The pathological role of integrin αv during aneurysm formation was confirmed by blockade of integrin αv with GLPG0187 in Fbn1C1039G/+ MFS mice. Results: iPSC–derived MFS SHF SMCs overexpress integrin αv relative to MFS NC and healthy control SHF cells. Furthermore, integrin αv downstream targets (FAK [focal adhesion kinase]/Akt Thr308 /mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment of MFS SHF SMCs with GLPG0187 reduced p-FAK/p-Akt Thr308 /mTORC1 activity back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS NC SMCs and control SMCs, which normalized with GLPG0187 treatment. In the Fbn1C1039G/+ MFS mouse model, integrin αv, p-Akt Thr308 , and downstream targets of mTORC1 proteins were elevated in the aortic root/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6–14 weeks) had reduced aneurysm growth, elastin fragmentation, and reduction of the FAK/Akt Thr308 /mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing. Conclusions: The integrin αv-FAK-Akt Thr308 signaling pathway is activated in iPSC SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-Akt Thr308 signaling in Fbn1C1039G/+ mice. Integrin αv blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.

01 Jan 2023·American journal of cancer research

Broad spectrum integrin inhibitor GLPG-0187 bypasses immune evasion in colorectal cancer by TGF-β signaling mediated downregulation of PD-L1.

Article

Author: Carlsen, Lindsey ; MacDonald, William J ; El-Deiry, Wafik S ; Verschleiser, Brooke ; Huntington, Kelsey E ; Zhou, Lanlan

Integrin receptors have long posed as a potentially attractive target for disrupting cancer hallmarks. Promising preliminary findings with integrin inhibition as an adjuvant to chemotherapy have not translated to clinical success. However, the effect of integrin inhibition on tumor-immune cell interactions remains largely unexplored. Further investigation could shed light on a connection between integrin signaling and immune checkpoint expression, opening the path for using integrin inhibitors to sensitize otherwise resistant tumors to immunotherapy. Fluorescently labeled wild-type HCT-116 colorectal cancer cells and TALL-104 T-cells were co-cultured and treated with GLPG-0187, a small molecule integrin inhibitor, at various doses. This assay revealed dose dependent cancer cell killing, indicating that integrin inhibition may be sensitizing cancer cells to immune cells. The hypothesized mechanism involves TGF-β-mediated PD-L1 upregulation in cancer cells. To investigate this mechanism, both WT and p53-/- HCT-116 cells were pre-treated with GLPG-0187 and subsequently with latent-TGF-β. Western blot analysis demonstrated that the addition of latent-TGF-β increased the expression of PD-L1 in cancer cells. Additionally, a low dose of integrin inhibitor rescued these effects, returning PD-L1 expression back to control levels. This indicates that the immunostimulatory effects of integrin inhibition may be due to downregulation of immune checkpoint PD-L1 on cancer cells. It must be noted that the higher dose of the drug did not reduce PD-L1 expression. This could potentially be due to off-target effects conflicting with the proposed pathway; however, these findings are still under active investigation. Ongoing proteomic experiments will include a larger range of both drug and latent-TGF-β doses. Probing for additional downstream markers of TGF-β and up-stream markers of PD-L1 will help to further elucidate this mechanism. Further co-culture experiments will also include anti-PD-L1 and anti-PD-1 therapy to investigate the viability of integrin inhibition as an adjuvant to immune checkpoint blockade.

100 Deals associated with GLPG-0187

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 2	Netherlands	Galapagos NV	01 Mar 2011
Metastatic Colorectal Carcinoma	Preclinical	United States	Brown University	04 Apr 2023

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