Attenuation of Murine Collagen-Induced Arthritis by a Novel, Potent, Selective Small Molecule Inhibitor of IκB Kinase 2, TPCA-1 (2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), Occurs via Reduction of Proinflammatory Cytokines and Antigen-Induced T Cell Proliferation

140 Background: BXCL701 (talabostat previously PT100) is an oral small molecule inhibitor of dipeptidyl peptidases (DPP) specifically DPP4, DPP8 and DPP9, which trigger macrophage cell death via pyroptosis resulting in proinflammatory stimulation of the innate immunity pathway. BXCL701 also inhibits fibroblast activation protein (FAP) releasing the FAP-mediated block of T-cell migration into the tumor. Expression of PD-L1 correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor responses were observed when BXCL701 was used with checkpoint inhibition. Methods: A phase 1b, multicenter study was undertaken. Eligible patients (pts) had progressing mCRPC (PCWG3), at least 1 line of systemic therapy and ≤ 2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anti-cancer therapy, and an ECOG PS of ≤ 2. Pts received fixed dose pembro (200mg IV q21 days) with escalating doses of BXCL701 (0.4mg and 0.6mg PO QD days 1-14 of 21-day cycles) using a 3 X 3 design. The key endpoints were safety and identification of the recommended phase 2 dose (RP2D) for the combination. Composite response (RECIST, PSA, CTC) was also assessed. Results: 3 pts were treated at the initial dose level for at least 4 cycles. All pts remain on treatment. No DLT or SAEs were reported. Grade 3 treatment related adverse events (TRAE) were limited to thrombocytopenia with transfusion in 1 pt. The only TRAE reported in more than one pt was hypocalcemia (2 pts). Safety assessment of BXCL701+pembro is ongoing at the final dose escalation cohort. As DPP9 is amplified in approximately 17% of treatment associated small cell/neuroendocrine prostate cancer (tSCNC) compared to 5% or less in the broader prostate cancer population, the Phase 2 portion of this study will be limited to patients with evidence of t-SCNC or de novo SCNC, an aggressive phenotype with poor outcomes. Conclusions: BXCL701 0.4mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days is safe in pts with mCRPC. The final dose escalation supporting RP2D will be presented. Clinical trial information: NCT03910660.

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Abstract 3741: Inhibition of PI3Kα kinase by a selective small molecule inhibitor suppresses B-cell proliferation and leukemic cell growth

10.1158/1538-7445.am2012-3741 ◽

2012 ◽

Cited By ~ 1

Author(s):

Swaroop Vakkalanka ◽

Srikant Viswanadha ◽

Prasanna R ◽

Meyyappan Muthuppalaniappan ◽

Babu Govindarajulu ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Growth ◽

B Cell ◽

Small Molecule ◽

Leukemic Cell ◽

Small Molecule Inhibitor ◽

Molecule Inhibitor

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Abstract 1640: A novel small molecule inhibitor of lysophosphatidic acid acyltransferase-beta inhibits pancreatic cancer cell proliferation and mTOR signaling

10.1158/1538-7445.am2014-1640 ◽

2014 ◽

Author(s):

Michelle A. Blaskovich ◽

Yunting Luo ◽

Yiyu Ge ◽

Saïd M. Sebti ◽

Harshani R. Lawrence ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Small Molecule ◽

Lysophosphatidic Acid ◽

Pancreatic Cancer Cell ◽

Small Molecule Inhibitor ◽

Mtor Signaling ◽

Cancer Cell Proliferation ◽

Molecule Inhibitor

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Specific Inhibitory Action of Anisodamine against a Staphylococcal Superantigenic Toxin, Toxic Shock Syndrome Toxin 1 (TSST-1), Leading to Down-Regulation of Cytokine Production and Blocking of TSST-1 Toxicity in Mice

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.12.3.399-408.2005 ◽

2005 ◽

Vol 12 (3) ◽

pp. 399-408 ◽

Cited By ~ 8

Author(s):

Saori Nakagawa ◽

Koji Kushiya ◽

Ikue Taneike ◽

Ken'ichi Imanishi ◽

Takehiko Uchiyama ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Proinflammatory Cytokines ◽

Toxic Shock Syndrome ◽

Inhibitory Effect ◽

Herbal Extract ◽

T Cell Proliferation ◽

Toxic Shock ◽

Toxic Shock Syndrome Toxin

ABSTRACT Toxic shock syndrome toxin 1 (TSST-1), produced by Staphylococcus aureus (including methicillin-resistant S. aureus), is a superantigenic toxin responsible for toxic shock syndrome as well as neonatal TSS-like exanthematous disease. TSST-1 exhibits its deleterious effects by leading to the abnormal proliferation of, e.g., Vβ2+ T cells and overproduction of proinflammatory cytokines. In the present study we examined the inhibitory effect of a Chinese herbal extract, anisodamine, on TSST-1 using human peripheral blood mononuclear cells (PBMCs). Anisodamine inhibited the production of proinflammatory cytokines better than interleukin-10 (an anti-inflammatory cytokine). The inhibitory effect of anisodamine was greater than that of any tropane alkaloid examined. Anisodamine acted directly on both monocytes and T cells in human PBMCs, and the effect was confirmed at the transcriptional level. Inhibition of NF-κB activation was also demonstrated. In contrast, no significant inhibition of Vβ2+ T-cell proliferation was observed. In mice injected with TSST-1, anisodamine treatment significantly decreased serum proinflammatory cytokine levels and prevented TSST-1-induced death. These results suggest that anisodamine specifically acts against the production of cytokines (inflammatory cytokines in particular) and not against Vβ2+ T-cell proliferation and that anisodamine may have a beneficial effect on TSST-1-associated disease.

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1-Benzyl-indole-3-carbinol is a highly potent new small molecule inhibitor of Wnt/β-catenin signaling in melanoma cells that coordinately inhibits cell proliferation and disrupts expression of microphthalmia-associated transcription factor isoform-M

Carcinogenesis ◽

10.1093/carcin/bgx103 ◽

2017 ◽

Vol 38 (12) ◽

pp. 1207-1217 ◽

Cited By ~ 5

Author(s):

Aishwarya Kundu ◽

Michelle G Khouri ◽

Sheila Aryana ◽

Gary L Firestone

Keyword(s):

Cell Proliferation ◽

Transcription Factor ◽

Small Molecule ◽

Small Molecule Inhibitor ◽

Melanoma Cells ◽

Molecule Inhibitor

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Regulation of IRE1α by the small molecule inhibitor 4μ8c in hepatoma cells

Endoplasmic Reticulum Stress in Diseases ◽

10.1515/ersc-2017-0001 ◽

2017 ◽

Vol 4 (1) ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Claire Stewart ◽

Andrea Estrada ◽

Paul Kim ◽

Dong Wang ◽

Yuren Wei ◽

...

Keyword(s):

Cell Proliferation ◽

Small Molecule ◽

Pancreatic Beta Cells ◽

Cell Types ◽

Small Molecule Inhibitor ◽

Hepatoma Cells ◽

Rnase Activity ◽

Molecule Inhibitor ◽

Target Effects

AbstractThe unfolded protein response (UPR) is activated in response to impairments of the folding environment in the endoplasmic reticulum (ER). The most conserved arm of the UPR, inositol-requiring ER-to-nucleus signaling protein (IRE1α), has been linked to the regulation of a diverse array of cellular processes including ER-associated degradation, inflammatory signaling, cell proliferation and membrane biogenesis. Recent studies have utilized the selective, small molecule inhibitor, 4μ8c, to examine the role of IRE1α endoribonuclease (RNase) activity in various cell types including multiple myeloma, mouse embryonic fibroblasts and pancreatic beta cells [1-5]. In the present study we utilized this inhibitor to examine the role of IRE1α RNase activity in hepatoma cells (H4IIE), specifically concentrating on cell proliferation and the identification of potential off target effects under both unstressed and stressed conditions. Experiments were performed in H4IIE hepatoma cells in the absence (control conditions (LG)) or presence (LG + Thapsigargin (Thap)) of ER stress. The presence of 4μ8c decreased IRE1α RNase activity, based on reduced splicing of X-box binding protein-1 (XBP1s) and regulated IRE1α-dependent decay of mRNA in both treatments and at concentrations ranging from 10-90 μM. Cell proliferation was significantly reduced at higher concentrations (> 60 μM 4μ8c) in unstressed cells and displayed a dose-response relationship with 4μ8c in both treatments. The presence of 4μ8c did not promote cytoxicity in either of the treatment conditions but higher concentrations of the inhibitor (60 μM) were associated with apparent off-target or compensatory responses that were not observed at 10 μM. Overall, the small-molecule inhibitor, 4μ8c is an effective inhibitor of IRE1α RNase activity in H4IIE cells. Potential off-target effects associated with this inhibitor require the use of multiple inhibitor concentrations in all experiments.

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