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MIF(Macrophage migration inhibitory factor)	1

AbstractMacrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduce UVB light–induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure. In addition to decreasing skin thickness and myeloperoxidase (MPO) activity, CPSI-1306 pretreatment increased keratinocyte apoptosis and p53 expression, decreased proliferation and phosphohistone variant H2AX (γ-H2AX), and enhanced repair of cyclobutane pyrimidine dimers. To examine the effect of CPSI-1306 on squamous carcinogenesis, mice were exposed to UVB for 10 weeks, followed by CPSI-1306 treatment for 8 weeks. CPSI-1306 dramatically decreased the density of UVB-associated p53 foci in non–tumor-bearing skin while simultaneously decreasing the epidermal Ki67 proliferation index. In addition to slowing the rate of tumor development, CPSI-1306 decreased the average tumor burden per mouse. Although CPSI-1306–treated mice developed only papillomas, nearly a third of papillomas in vehicle-treated mice progressed to microinvasive SCC. Thus, MIF inhibition is a promising strategy for prevention of the deleterious cutaneous effects of acute and chronic UVB exposure.Implications: Macrophage migration inhibitory factor is a viable target for the prevention of UVB-induced cutaneous SSCs. Mol Cancer Res; 12(9); 1292–302. ©2014 AACR.

01 Oct 2012·Langenbeck's Archives of SurgeryQ3 · MEDICINE

The novel orally active guanylhydrazone CPSI-2364 prevents postoperative ileus in mice independently of anti-inflammatory vagus nerve signaling

Q3 · MEDICINE

Article

Author: T. Sielecki ; B. Stoffels ; D. Pantelis ; M. Lysson ; S. Wehner ; J. C. Kalff ; T. O. Vilz ; G. S. Hong ; N. Sommer

PURPOSEPostoperative ileus (POI) is an iatrogenic complication of abdominal surgery, mediated by a severe inflammation of the muscularis externa (ME). Previously, we demonstrated that intravenous application of the tetravalent guanylhydrazone semapimod (CNI-1493) prevents POI, but the underlying mode of action could not definitively be confirmed. Herein, we investigated the effect of a novel orally active salt of semapimod (CPSI-2364) on POI in rodents and distinguished between its inhibitory peripheral and stimulatory central nervous effects on anti-inflammatory vagus nerve signaling.METHODSDistribution of radiolabeled orally administered CPSI-2364 was analyzed by whole body autoradiography and liquid scintillation counting. POI was induced by intestinal manipulation with or without preoperative vagotomy. CPSI-2364 was administered preoperatively via gavage in a dose- and time-dependent manner. ME specimens were assessed for p38-MAP kinase activity by immunoblotting, neutrophil extravasation, and nitric oxide production. Furthermore, in vivo gastrointestinal (GIT) and colonic transit were measured.RESULTSAutoradiography demonstrated a near-exclusive detection of CPSI-2364 within the gastrointestinal wall and contents. Preoperative CPSI-2364 application significantly reduced postoperative neutrophil counts, nitric oxide release, GIT deceleration, and delay of colonic transit time, while intraoperatively administered CPSI-2364 failed to improve POI. CPSI-2364 also prevents postoperative neutrophil increase and GIT deceleration in vagotomized mice.CONCLUSIONSOrally administered CPSI-2364 shows a near-exclusive dispersal in the gastrointestinal tract and effectively reduces POI independently of central vagus nerve stimulation. Its efficacy after single oral dosage affirms CPSI-2364 treatment as a promising strategy for prophylaxis of POI.

15 Apr 2012·Cancer Research

Abstract 159: Macrophage Migration Inhibitory Factor (MIF) enhances proliferation and expression of tumorigenic cytokines in a bladder cancer cell line

Author: Taylor, John Arthur ; Sielecki, Thais M. ; Pilbeam, Carol ; Choudhary, Shilpa ; Pruitt, James R.

AbstractBackground: MIF is a proinflammatory cytokine with regulatory properties over tumor suppressor proteins involved in bladder cancer. We have previously reported that the absence of MIF in transgenic mice or the use of a small molecule oral inhibitor of MIF (CPSI-1306, Cytokine PharmaSciences, Inc, King of Prussia, PA) leads to decreased angiogenesis and invasive potential in the BBN mouse model of bladder cancer. The objective of this study was to evaluate potential pathways of MIF activity in a cell culture model. Methods: High grade, metastatic HTB-5 bladder cancer cells were treated with rhMIF 1-100 ng/ml (CPSI). Measurements included cell counts, proliferation by 3H-thymidine incorporation (TdR), phosphorylated and total ERK by Western analysis and mRNA expression of TNF-α, IL-6, VEGF and CD74 (putative receptor for MIF) by real time PCR. CPSI-1306 (0.5-500 nM) was tested for its ability to decrease ERK phosphorylation. Results: MIF 100 ng/ml increased cell counts 2-fold (p<0.01) on culture days 2-4. MIF increased TdR, normalized to cell numbers, 30% (p<0.01). MIF (1-100 ng/ml) stimulated ERK phosphorylation in a dose dependent manner, which was abrogated by the addition of CPSI-1306 at doses above 5 nM. A specific inhibitor of ERK (PD98059, 50 μm) blocked the MIF stimulated increase in cell number. MIF treatment for 24 hrs increased mRNA expression of the agiogenic factor VEGF and the cytokine TNF-α 2-fold (p<0.01). IL-6 mRNA was unchanged. mRNA levels for the putative MIF receptor, CD74, increased 1.3 fold with treatment (p=0.01). Conclusion: MIF increased ERK phosphorylation, which was blocked by CPSI-1306, a small molecule inhibitor of MIF. MIF also increased cell proliferation via an ERK pathway. These data, along with the increased cytokine expression, provide a potential explanation for the decreased angiogenesis and invasion seen in our in vivo murine models using global knockout of MIF or CPSI-1306. This study is the first to begin to elucidate mechanistic pathways involved in MIFs role in bladder cancer and possible pathways involved in CPSI-1306 inhibition. Funding Source: ACS MRSG-08-270-01-CCE, NIH RO1DK48361Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 159. doi:1538-7445.AM2012-159

100 Deals associated with Cytokine PharmaSciences, Inc.

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100 Translational Medicine associated with Cytokine PharmaSciences, Inc.

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Pipeline

Pipeline Snapshot as of 17 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

Imalumab ( MIF )	Colorectal Cancer More	Phase 2
Semapimod Mesylate ( CRAF x Cytokines )	Chemotherapy-induced damage More	Discontinued
CPSI-306	-	Pending
Fibrovax	Neoplasms More	Pending
CNI-H0294	Malaria More	Pending