TTI-101 oral

Oct4 small interfering (Oct4 siRNA) or STAT3 inhibitor C188-9 was also co-cultured with cells in some experiments, respectively...Furthermore, T3-induced cellular growth was reduced by Oct4 siRNA, which indicates that T3 regulates cellular development through OCT4. These findings suggest that T3 increases cellular development via OCT4, which is mediated by phosphorylation of STAT3, and TR is also involved in these processes.

P2, N=75, Recruiting, Tvardi Therapeutics, Incorporated | Trial completion date: Mar 2025 --> Jul 2025

After being treated with C188-9, EBV + B cell-derived exosomes were no longer able to stimulate the expression of IL-10/PD-L1 in CTCL cells...Exosomes derived from EBV + B could induce phosphorylation of STAT3 in CTCL cells, leading to the overexpression of IL-10/PD-L1. Our findings might shed light on new directions for understanding immune evasion in EBV-T/NK-LPDs.

P1/2, N=6, Completed, Tvardi Therapeutics, Incorporated | Active, not recruiting --> Completed

P1, N=60, Active, not recruiting, Tvardi Therapeutics, Incorporated | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

P1/2, N=35, Recruiting, University of Colorado, Denver | Initiation date: Dec 2024 --> Jan 2024

P1/2, N=6, Active, not recruiting, Tvardi Therapeutics, Incorporated | Recruiting --> Active, not recruiting | N=53 --> 6 | Trial completion date: Feb 2025 --> Jun 2024 | Trial primary completion date: Dec 2024 --> Jun 2024

P1/2, N=35, Recruiting, University of Colorado, Denver | Not yet recruiting --> Recruiting | Initiation date: Dec 2023 --> Dec 2024

P1/2, N=154, Recruiting, Tvardi Therapeutics, Incorporated

P1/2, N=53, Recruiting, Tvardi Therapeutics, Incorporated

P1/2, N=35, Not yet recruiting, University of Colorado, Denver

P1, N=33, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: Oct 2023 --> Oct 2024

P1, N=60, Active, not recruiting, Tvardi Therapeutics, Incorporated | Trial completion date: Oct 2023 --> Jun 2024 | Trial primary completion date: Oct 2023 --> Mar 2024

P1/2, N=35, Not yet recruiting, University of Colorado, Denver

P1/2, N=53, Recruiting, Tvardi Therapeutics, Incorporated | Phase classification: P1b/2 --> P1/2

P1/2, N=154, Recruiting, Tvardi Therapeutics, Incorporated | Phase classification: P1b/2 --> P1/2

IL-6 treatment improved polarization of M2 subtypes and the expression of PD-1 in bone marrow-derived macrophages (BMDMs); whereas both aIL-6 and STAT3 inhibitor C188-9 suppressed the expression of PD-1 and SIRPα in BMDMs...Thereby, SIRPα and IL-6 form a positive feedback loop and regulate each other through STAT3 signaling in macrophages. The increased SIRPα/IL-6 axis may promote immune suppressive environment and lung cancer growth, which may be a potential target for clinical treatment.

In conclusion, our data suggests that the inhibitors of Src or STAT3 could function as radiosensitizers or CSC targeting agents for TNBC radiotherapy.

P1, N=33, Not yet recruiting, M.D. Anderson Cancer Center

The molecular mechanism studies based on transcriptomics and proteomics analyses indicated that XYA-2 might exert its anticancer activity by synergistically inhibiting the expression of MYC and SLC39A10, two downstream genes of STAT3 in vitro and in vivo. Together, these findings suggested that XYA-2 may be a potent STAT3 inhibitor for treating gastric cancer, and dual inhibition of MYC and SLC39A10 may be an effective therapeutic strategy for STAT3-activated cancer.

The aim of our study is to examine the preclinical anticancer efficacy of STAT3 inhibitors [TTI-101 (C188-9) and SH5-07] in 3D (spheroid and tumoroid) invitro models of BC...Drug treated BC spheroids/tumoroids also showed reduction in CD44 (BC stemness and invasion marker) and induction of cGAS-STING pathway (cGAS, STING, TBK1, and IRF3) in comparison to the control. These findings indicate that STAT3 inhibitors, TTI-101 and SH5-07, could inhibit bladder cancer by suppressing STAT3 pathway activation and therefore warrant further study in vivo.

P1b/2, N=154, Recruiting, Tvardi Therapeutics, Incorporated | Not yet recruiting --> Recruiting | Initiation date: Nov 2022 --> Mar 2023

By contrast, pretreatment with the STAT3 inhibitor C188-9 or the PI3K/AKT/mTOR inhibitor LY3023414 reversed the LIF-induced inhibition of RGC loss. These results suggested that exogenous LIF treatment inhibited the retinal damage induced by AOH, which was associated with the activation of STAT3 and mTOR/p70S6K signaling. Therefore, LIF may serve a role in neuroprotection for glaucoma treatment.

We used an animal model of CD consisting of intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid and examined the severity of CD in transgenic-mice that express only STAT3α (∆/∆), as well as in wild-type (WT) mice administered TTI-101 (formerly C188-9), a small molecule STAT3 inhibitor...TTI-101 treatment also increased apoptosis of pathogenic CD4 T cells and reduced colon levels of IL-17-positive cells. Our results indicate that STAT3 contributes to CD and that targeting of STAT3 with TTI-101 may be a useful approach to treating CD.

The cytotoxic effects by mCRPs knock-down were potentiated in the cells co-treated with doxorubicin (Dox). In addition, STAT3, STAT6, and p38 MAPK inhibitors, including C188-9, AS1517499 and SB203580 effectively reduced the expression of CD46 in the treated colon cells, associated with increased cell apoptosis and LDH release. Further study with mouse model revealed that mCRPs knockdown by mCRPs-shRNA significantly reduced colon cancer growth, associated with increased expression of Bax, cleaved caspase-3 and C5b-9 deposition, but reduced expression of Bcl-2, IL-6 and IL-1beta in tumor tissues of nude mice transplanted with SW620 cells. Thereby, mCRPs expression in human colon cancer cells were upregulated by STAT3/STAT6/p38 MAPK signaling and mCRPs knockdown reduced colon cancer growth in mice through inducing tumor cell apoptosis.

Background: Histone deacetylase inhibitors (HDACis), such as vorinostat and romidepsin, are effective treatment agents for various T-cell lymphomas, including cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia...Moreover, resistant cell lines showed increased sensitivity to the STAT3-selective inhibitor C188-9. However, compared to the controls, the resistant cell lines showed no difference in their sensitivity towards the JAK1/2 inhibitor ruxolitinib... Activation of STAT3 in HDACi-resistant CTCL cells was enhanced by gp130, which contributed to their resistance. These results suggest that STAT3 could be the new therapeutic target in HDACi-resistant CTCL and that gp130/STAT3 inhibition could be an important therapeutic strategy. To further elucidate the detailed mechanism of HDACi resistance, analysis of the pathways activating STAT3 without JAK and the target proteins of STAT3 is warranted.

In this study, the BCL-XL inhibitor A1331852, MCL1-inhibitor S63845, dual PI3K-mTOR inhibitor bimiralisib (PQR309), BMI-1 inhibitor unesbulin (PTC596), MEK-inhibitor trametinib (GSK1120212), and STAT3 inhibitor C-188-9 were assessed as single agents and in combination with venetoclax, for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. For the venetoclax and bimiralisib combination treatment, responders were enriched for IDH2 and FLT3 mutations, whereas non-responders were associated with PTPN11 mutations. The combination of PI3K/mTOR dual pathway inhibition with bimiralisib and BCL2 inhibition with venetoclax has emerged as a candidate treatment in IDH2- and FLT3-mutated AML.

P1, N=60, Active, not recruiting, Tvardi Therapeutics, Incorporated | Recruiting --> Active, not recruiting

The combination of ABT-199 with JAK1/2 inhibitor Ruxolitinib or STAT3 inhibitors Stattic and C188-9 increased malignant B cell death. In summary, we show that IFN-γ enhanced CLL cells resistance to ABT-199 at least in part by up-regulating BCL-2, MCL-1 and BCL-xL expression via JAK1/2-STAT3 pathway, and thus blocking this pathway with inhibitors increased ABT-199 efficiency to induce CLL cell apoptosis, suggesting a potential therapeutically relevant combination to overcome ABT-199 resistance.

These results demonstrated that exosomal miR-761 modulated the tumor microenvironment via SOCS2/JAK2/STAT3 pathway-dependent activation of CAFs. Our findings may inspire new strategies for HCC prevention and therapy.

MiR-630 constrained the progression of NSCLC by inhibiting JAK2/STAT3 pathway and downregulating VIM expression.

P1b/2, N=53, Recruiting, Tvardi Therapeutics, Incorporated | Initiation date: Jun 2022 --> Sep 2022

P1b/2, N=53, Recruiting, Tvardi Therapeutics, Incorporated | Not yet recruiting --> Recruiting

Results CTCL cell lines resistant to vorinostat were also resistant to romidepsin, suggesting that vorinostat-resistant cell lines were cross-resistant to other HDACis...Moreover, resistant cell lines showed increased sensitivity to the STAT3-selective inhibitor, C188-9...Conclusion Activation of STAT3 in HDACi-resistant CTCL cells was enhanced via gp130, which contributed to their resistance. These results suggested that STAT3 could be a new therapeutic target in HDACi-resistant CTCL, and gp130/STAT3 inhibition could be an important therapeutic strategy.

For in vivo experiments, CC-LR mice were treated daily with 50 mg/kg TTI-101 by oral gavage from 10 to 14 weeks of age to model a preventative regimen or from 14 to 18 weeks of age to survey the treatment effect on established tumors...The ongoing combination treatments and the 14-18-week cohorts will elucidate the timing of treatments as well as reveal if by targeting the inflammatory TME we are able to improve response to ICB. Funded by: R01 grant from NIH/NCI (R01CA225977)

Recent, some inhibitors of IL-6/STAT3 have been development, such as S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb), Madindoline A (Inhibits the dimerization of IL-6/IL-6R/gpl30 trimeric complexes), C188-9 and Curcumin (Inhibits STAT3 phosphorylation), etc. for treatment of cancers. Overall, consideration of the IL-6/STAT3 signaling pathway, and its role in the carcinogenesis and progression of HCC will contribute to the development of potential drugs for targeting treatment of liver cancer.

P1, N=60, Recruiting, Tvardi Therapeutics, Incorporated | Trial completion date: Dec 2021 --> Oct 2023 | Trial primary completion date: Dec 2021 --> Oct 2023

P1, N=47, Recruiting, Tvardi Therapeutics, Incorporated | N=30 --> 47 | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Dec 2021

Enrollment to the HCC dose expansion began in February 2021 . Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice.

HCC-immune humanized mouse models are suitable for identifying targets from cancer and immune components and testing combinational therapies.

Niclosamide represents a promising candidate for repurposing to potentiate the anticancer activity of chemotherapeutic drugs.