P2, N=2, Terminated, Weill Medical College of Cornell University | N=37 --> 2 | Trial completion date: Sep 2025 --> Jul 2024 | Recruiting --> Terminated; Low accrual

Activation of the TGFβ/Smad signaling pathway was found involved in AMIGO2-induced EMT, and treatment with the TGFβ receptor inhibitor LY2109761 suppressed AMIGO2-induced EMT...These results suggest that the nuclear translocation of AMIGO2 induces EMT to promote CRC invasion by activating the TGFβ/Smad signaling pathway. Thus, AMIGO2 is an attractive therapeutic target for inhibiting EMT and metastatic CRC progression.

Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable ICHS9 compliant profile for the intended-to-treat cancer patients.

In human RPE cells (ARPE-19), TGF-β administration suppressed mRNA and protein levels of LRAT; and vactosertib, a selective inhibitor of TGF-β receptor kinase type 1, reversed the effect of TGF-β. These findings suggest that hypertension-induced retinal neurodegeneration involves inflammation, apoptosis, necroptosis, and disrupted retinoid metabolism, providing potential therapeutic targets for hypertensive retinopathy.

Of these, compounds 13b (IC50 = 0.130 μM) and 15a (IC50 = 0.130 μM) showed the highest inhibitory activities against ALK5 kinase, with activities similar to the positive control LY-2157299...Compounds 13b and 15a did not show toxicity in A549 cells up to the maximum concentration of 50 μM, and effectively inhibited TGF-β1-induced Smad-signaling and cell motility in A549 cells. The results indicate that compounds 13b and 15a are worth of further development as anticancer agents.

Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

The role of TGFβ was interrogated via ALK5 inhibitor (SB-525334) administration...We have developed and characterized a new mouse model of PSC-CCA, termed SB CCA.Mdr2-/-, which features reliable tumor induction in PSC-like background of biliary injury and fibrosis. Global gene expression alterations were identified and standardized tools, including automated whole slide image analysis methodology for tumor burden and feature analysis, were established to enable systematic research into PSC-CCA biology and formal pre-clinical drug testing.

No abstract available

P1, N=223, Active, not recruiting, Eli Lilly and Company | Trial completion date: Aug 2024 --> Aug 2025

Mechanistically, MWA collaborated with SB-525334 inhibitor inactivated the TGF-β1/Smad2/Smad3 pathway. TGF-β1 inhibitor enhances the therapeutic effect of MWA on HCC.

In 2D and 2.5D cultures, treatment with β-estradiol with or without EGF or TGF-β decreased CGN expression and the epithelial permeability barrier and enhanced cell migration, and pretreatment with EW7197+AG1478, U0126 or an anti-IL-6 antibody prevented this. In conclusion, CGN, with tTJ proteins might suppress the malignancy of human EEC and its complex proteins are sensitive to estrogen and growth factors derived from stromal cells.

Herein, we report the discovery of a series of novel thiazole derivatives as potent inhibitors of ALK5, a serine-threonine kinase which is responsible for TGF-βsignal transduction. Compound 29b was identified as a potent inhibitor of ALK5 with an IC50 value of 3.7 nM with an excellent kinase selectivity.

P1, N=25, Completed, Agomab Spain S.L. | Active, not recruiting --> Completed

P1, N=24, Active, not recruiting, Agomab Spain S.L.

P1/2, N=120, Active, not recruiting, MedPacto, Inc. | Phase classification: P1b/2a --> P1/2 | N=67 --> 120 | Trial completion date: Aug 2023 --> Aug 2024 | Trial primary completion date: Jun 2021 --> May 2024

GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies.

Cellular thermal shift assay and western blotting revealed that AZ12601011 directly bound with TGFβRI and blocked the activation of Smad3 downstream. In conclusion, our findings revealed that AZ12601011 attenuated PQ-induced multiple organ fibrosis by blocking the TGF-β/Smad3 signalling pathway, suggesting its potential for PQ poisoning treatment.

In this review, we shed light on the current ATP-competitive inhibitors of ALK5 through diverse heterocyclic based scaffolds that are in clinical or pre-clinical phases of development. Moreover, we focused on the binding interactions of the compounds to the ATP binding site and the structure-activity relationship (SAR) of each scaffold, revealing new scopes for designing novel candidates with enhanced selectivity and metabolic profiles.

P2, N=90, Recruiting, Agomab Spain S.L. | N=36 --> 90 | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

SOX18 promoted the accumulation of immunosuppressive TAMs and Tregs in microenvironment by transactivating CXCL12 and PD-L1. CXCR4 inhibitor or TGFβR1 inhibitor in synergy with anti-PD-L1 represented a promising combination strategy to suppress HCC progression and metastasis.

P1/2, N=148, Completed, Zhejiang Genfleet Therapeutics Co., Ltd. | Recruiting --> Completed | Trial completion date: Jun 2024 --> Dec 2023

Vactosertib and imatinib combination was well-tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-β inhibitor, in this rare and difficult-to-treat desmoid tumor.

P2, N=76, Recruiting, MedPacto, Inc.

P1/2, N=48, Recruiting, MedPacto, Inc. | Not yet recruiting --> Recruiting

EW-7197 (a TGF-β receptor inhibitor), AG1478 (an EGFR inhibitor) and SP600125 (a JNK inhibitor) affected the epithelial permeability barrier, cell migration and mitochondrial metabolism and prevented the changes induced by TGF-β and EGF in 2D and 2.5D cultures. In conclusion, TGF-β and EGF promoted the malignancy of endometrial cancer via interplay among the epithelial permeability barrier, cell migration and mitochondrial metabolism. EW-7197 and AG1478 may be useful as novel therapeutic treatments options for endometrial cancer.

P1, N=76, Recruiting, Agomab Spain S.L.

One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.

P2, N=36, Recruiting, Agomab Spain S.L.

The TGF-β1 signaling was interfered by LY2109761, a TGF-β receptor 1 (TβR1) inhibitor, or TGF-β1 neutral antibody...IFT88 siRNA or KIF3a siRNA impaired PC formation resulted in an aggravated DNA damage in bystander cells, while elevated PC formation by CytoD or STIL siRNA resulted in a decrease of DNA damage. Furthermore, TGF-β1 induced more DNA damages in S phases cells which showed lower PC formation rate and less DNA damages in G /G phase cells which showed higher PC formation rate. This study demonstrates the particular role of primary cilia during RCM induced DNA damages through TGF-β1 signaling restriction and thereby provides a functional link between primary cilia and RIBEs.

The molecular docking analyses in this study predict that rutin occludes the active site of TβRI and inhibits SMAD-mediated fibrotic signaling pathways in lung fibrosis. These findings highlight the potential of rutin as a promising anti-fibrotic prodrug for lung fibrosis and other TGF-β-induced fibrotic and cancer-related diseases; however, further studies are required to validate its safety and effectiveness in other experimental models.

P2, N=36, Recruiting, Agomab Spain S.L. | Phase classification: P2a --> P2

P2, N=37, Recruiting, Weill Medical College of Cornell University | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2023 --> Sep 2024

Despite increased expression and interaction between TGF-β and HIF-1α pathways in some cancers, in melanoma, inhibition of either pathway alone may have a stronger effect on tumor inhibition than simultaneous inhibition of both pathways. The synergistic effects may be context-dependent and should be further evaluated in different cancer types.

P1/2, N=202, Recruiting, Nanjing Leads Biolabs Co.,Ltd | Trial primary completion date: Oct 2023 --> Oct 2024

This study demonstrating the potent anti-tumor effects of Vactosertib against CRC progression. Our results clearly suggest that this inhibitor could be a promising agent reducing CRC tumor progression when administered either alone or in combination with standard treatment in CRC patients.

To probe the tumor intrinsic anti-myeloma activity of vactosertib, we first determined the relative effect of vactosertib compared to the IMiDs pomalidomide and lenalidomide (Fig. Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, Vactosertib reduced TGFβ in patient bone marrow and suppressed PD-1 expression on CD8+ T-cells and lead to reduction of PD-L1/PD-L2 expression on CD138+ cells and enhanced autologous T-cell cytotoxicity. Taken together, our results support the safety and efficacy of vactosertib to treat RRMM and revealed that vactosertib modulates the T-cell immunophenotype and reinvigorates T-cell fitness.

Furthermore, in selected samples, addition of Luspatercept led to greater maturation of erythrocytes. Our current results support the preclinical in vitro efficacy of ALK5 inhibitors IOA-359 and IOA-360 alone and in combination with Luspartercept, highlighting their potential for further development and clinical testing in MDS/AML.

Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

P1, N=223, Active, not recruiting, Eli Lilly and Company | Trial completion date: Aug 2023 --> Aug 2024

ALK5 inhibitor (SB-525334, 300 mg/kg in diet) or placebo diet was administered into tumor-bearing mice to interrogate the functional role of TGFβ signaling in our model... We established a new high-fidelity cholangiocarcinoma model in mice, termed SB CCA.Mdr2-/-, which recapitulates the increased susceptibility to CCA in the setting of progressive biliary injury and fibrosis observed in PSC. Furthermore, pharmacological targeting of ALK5 in our model suggests that TGFβ signaling functionally drives CCA tumorigenesis and promotes desmoplastic reaction.

We demonstrated that pretreatment with a TGFβR1 inhibitor (LY3200882) significantly augmented the efficacy of CAR-T therapy and improved overall survival of mice bearing large established tumors...Based on these results, we next evaluated TGFβ-resistant CAR-T cells in vivo and demonstrated that blocking TGFβ-signaling through TGFβR2 knockout augmented the efficacy of CAR-T cells in a large immunosuppressive GBM tumor model in syngeneic mice. Conclusions Collectively, our results indicate that inhibiting the TGFβ pathway either in TME or CAR T cells is essential for enhancing CAR-T cell efficacy in GBM.