Chemistry

1) Discovery of N‑((4-([1,2,4]triazolo[1,5‑a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)‑1H‑imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): A highly potent, selective, and orally bioavailable inhibitor of TGF‑β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent. Journal of Medicinal Chemistry, May 2014. https://doi.org/10.1021/jm500115w

2) Preparation of 2-pyridyl substituted imidazoles as therapeutic ALK5 and/or ALK4 inhibitors. US8080568 B1 (2011)

3) Synthesis and preclinical evaluation of [11C]LR111 and [18F]EW-7197 as PET tracers of the activin-receptor like kinase-5. Nuclear Medicine and Biology, September–October 2022, https://doi.org/10.1016/j.nucmedbio.2022.05.003

Inflammatory bowel disease (IBD)

1) Increase in epithelial permeability and cell metabolism by high mobility group box 1, inflammatory cytokines and TPEN in Caco-2 Cells as a novel model of inflammatory bowel disease. International Journal of Molecular Sciences, November 2020. https://doi.org/10.3390/ijms21228434

2) Development of an oral bentonite-based modified-release freeze-dried powder of vactosertib: Pharmacokinetics and anti-colitis activity in rodent models of ulcerative colitis. International Journal of Pharmaceutics, March 2020. https://doi.org/10.1016/j.ijpharm.2020.119103

3) Composition comprising clay mineral complex for prevention, alleviation and treatment of inflammatory bowel disease, preparation method for composition, and method for alleviation and treatment for inflammatory bowel disease. WO2020209476 A1; KR2035481 B1 (2019)

4) EW-7197 prevents ulcerative colitis-associated fibrosis and inflammation. Journal of Cellular Physiology, November 2018. https://doi.org/10.1002/jcp.27823

Eye disease

1) Composition or method including (T)EW-7197 for treating or preventing corneal endothelial diseases. WO2019117254 A1; US2021077476 A1

2) Composition or method containing an ALK5 inhibitor, EW-7197. US20230047393 A1; WO2023013993 A1

Adhesion

1) Different routes of administering EW-7197 versus EW-7197⋅HBr for preventing peritoneal adhesion in a rat model. Surgery, April 2023. https://doi.org/10.1016/j.surg.2022.11.016

2) Novel oral transforming growth factor-β signaling inhibitor potently inhibits postsurgical adhesion band formation. Journal of Cellular Physiology, July 2019. https://doi.org/10.1002/jcp.29053

3) EW-7197, an oral transforming growth factor β type I receptor kinase inhibitor, for preventing peritoneal adhesion formation in a rat model. Surgery, August 2018. https://doi.org/10.1016/j.surg.2018.07.005

Liver fibrosis, NASH

1) Method for treating non-alcoholic steatohepatitis through co-administration of curcumin derivative and TGF-β receptor inhibitor. WO2022270760 A1

2) TGF‑β type I receptor kinase inhibitor EW-7197 suppresses cholestatic liver fibrosis by inhibiting HIF1ɑ-induced epithelial mesenchymal transition. Cellular Physiology and Biochemistry, February 2016. https://doi.org/10.1159/000438651

3) EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-β/Smad and ROS signaling. Cellular and Molecular Life Sciences, May 2015. https://doi.org/10.1007/s00018-014-1798-6

Kidney fibrosis

1) EW-7197 attenuates the progression of diabetic nephropathy in db/db mice through suppression of fibrogenesis and inflammation. Endocrinology and Metabolism, February 2022. https://doi.org/10.3803/EnM.2021.1305

2) EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-β/Smad and ROS signaling. Cellular and Molecular Life Sciences, May 2015. https://doi.org/10.1007/s00018-014-1798-6

Lung fibrosis

1) An in silico study on pulmonary fibrosis inhibitors from Tinospora cordifolia and Curcuma longa targeting TGF-β RI. Journal of Biomolecular Structure and Dynamics, January 2022. https://doi.org/10.1080/07391102.2022.2029772

2) Study of the common activating mechanism of apoptosis and epithelial-to-mesenchymal transition in alveolar type II epithelial cells. Respiratory Physiology & Neurobiology, February 2021. https://doi.org/10.1016/j.resp.2020.103584

3) Novel high–throughput myofibroblast assays identify agonists with therapeutic potential in pulmonary fibrosis that act via EP2 and EP4 receptors. PLoS ONE, November 2018. https://doi.org/10.1371/journal.pone.0207872

4) EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-β/Smad and ROS signaling. Cellular and Molecular Life Sciences, May 2015. https://doi.org/10.1007/s00018-014-1798-6

Cardiac fibrosis

1) Long non-coding RNA 554 promotes cardiac fibrosis via TGF-β1 pathway in mice following myocardial infarction. Frontiers in Pharmacology, December 2020. https://doi.org/10.3389/fphar.2020.585680

Radiation-induced fibrosis

1) Radiotherapy-induced oxidative stress and fibrosis in breast cancer are suppressed by vactosertib, a novel, orally bioavailable TGF-β/ALK5 inhibitor. Scientific Reports, September 2022. https://doi.org/10.1038/s41598-022-20050-9

COVID-19

1) Inhibitors of activin receptor-like kinase 5 interfere with SARS-CoV-2 S-protein processing and spike-mediated cell fusion via attenuation of furin expression. Viruses, June 2022. https://doi.org/10.3390/v14061308

Stent-induced granulation tissue formation/fibrosis

1) EW-7197 eluting nano-fiber covered self-expandable metallic stent to prevent granulation tissue formation in a canine urethral model. PLoS ONE, February 2018. https://doi.org/10.1371/journal.pone.0192430

2) EW-7197, an activin-like kinase 5 inhibitor, suppresses granulation tissue after stent placement in rat esophagus. Gastrointestinal Endoscopy, July 2017. http://doi.org/10.1016/j.gie.2017.01.013

Penile fibrosis

1) Vactosertib, a novel, orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaques in a rat model of Peyronie’s disease. The World Journal of Men’s Health, October 2020. https://doi.org/10.5534/wjmh.190071

Wound repair and fibrosis

1) EW-7197, a transforming growth factor-beta type I receptor kinase inhibitor, ameliorates acquired lymphedema in a mouse tail model. Lymphatic Research and Biology, October 2020. https://doi.org/10.1089/lrb.2018.0070

2) Inhibition of fibrosis to combat lymphedema. Lymphatic Research and Biology, October 2020. https://doi.org/10.1089/lrb.2020.29093.sr

Oncology

1) Combination treatment of T1-44, a PRMT5 inhibitor with Vactosertib, an inhibitor of TGF-β signaling, inhibits invasion and prolongs survival in a mouse model of pancreatic tumors. Cell Death & Disease, February 2023. https://doi.org/10.1038/s41419-023-05630-5

2) Therapeutic implications of TGF-β pathway in Desmoid tumor based on comprehensive molecular profiling and clinicopathological properties. Cancers, December 2022. https://doi.org/10.3390/cancers14235975

3) Phase 1b study of vactosertib in combination with oxaliplatin with 5FU/LV (FOLFOX) in patients with metastatic pancreatic cancer who have failed first-line gemcitabine/nab-paclitaxel. Journal of Clinical Oncology, June 2022. https://doi.org/10.1200/JCO.2022.40.16_suppl.e16299

4) Phase 1b study of vactosertib in combination with nal-IRI plus 5FU/LV in patients with metastatic pancreatic ductal adenocarcinoma who failed first-line gemcitabine/nab-paclitaxel. Journal of Clinical Oncology, January 2022. https://doi.org/10.1200/JCO.2022.40.4_suppl.TPS632

5) LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer. Journal of Experimental & Clinical Cancer Research, October 2022. https://doi.org/10.1186/s13046-022-02516-w

6) Co-treatment with vactosertib, a novel, orally bioavailable activin receptor-like kinase 5 inhibitor, suppresses radiotherapy-induced epithelial-to-mesenchymal transition, cancer cell stemness, and lung metastasis of breast cancer. Radiology and Oncology, June 2022. https://doi.org/10.2478/raon-2022-0012

7) RKIP induction promotes tumor differentiation via SOX2 degradation in NF2-deficient conditions. Molecular Cancer Research, March 2022. https://doi.org/10.1158/1541-7786.MCR-21-0373

8) Autotaxin (ATX) inhibitor for the treatment of pancreatic cancer. WO2022258693 A1

9) Tumor microenvironment based on PD-L1 and CD8 T-cell infiltration correlated with the survival of MSS mCRC patients treated vactosertib in combination with pembrolizumab. Journal for ImmunoTherapy of Cancer, November 2021. https://doi.org/10.1136/jitc-2021-SITC2021.074

10) Spatial analysis of tumor-infiltrating lymphocytes correlates with the response of metastatic colorectal cancer patients treated with vactosertib in combination with pembrolizumab. Journal for ImmunoTherapy of Cancer, November 2021. https://doi.org/10.1136/jitc-2021-SITC2021.823

11) Efficacy and safety of vactosertib and pembrolizumab combination in patients with previously treated microsatellite stable metastatic colorectal cancer. Journal of Clinical Oncology, May 2021. https://doi.org/10.1200/JCO.2021.39.15_suppl.3573

12) Phase 1b trial of vactosertib in combination with pomalidomide in relapsed multiple myeloma: A corticosteroid-free approach by targeting TGF-β signaling pathway. Journal of Clinical Oncology, May 2021. https://doi.org/10.1200/JCO.2021.39.15_suppl.8039

13) Beneficial effect of vactosertib combined with nal-IRI5-FU/LV in pancreatic cancer treatment. Cancer Research, July 2021. https://doi.org/10.1158/1538-7445.AM2021-2902

14) Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms. Cancer Cell, November 2021. https://doi.org/10.1016/j.ccell.2021.09.003

15) Reducing tumor invasiveness by ramucirumab and TGF-β receptor kinase inhibitor in a diffuse-type gastric cancer patient-derived cell model. Cancer Medicine, September 2021. https://doi.org/10.1002/cam4.4259

16) Penetration cascade of size switchable nanosystem in desmoplastic stroma for improved pancreatic cancer therapy. ACS Nano, September 2021. https://doi.org/10.1021/acsnano.0c08860

17) Co-inhibition of SMAD and MAPK signaling enhances 124I uptake in BRAF-mutant thyroid cancers. Endocrine-Related Cancer, May 2021. https://doi.org/10.1530/ERC-21-0017

18) Use of inhibitors of TGFβ/ActivinB signaling pathway for the treatment of patients suffering from medulloblastoma group 3. WO2021047775 A1

19) Vactosertib and durvalumab as second or later line treatment for PD-L1 positive non-small cell lung cancer: Interim result. Journal for ImmunoTherapy of Cancer, November 2020. https://doi.org/10.1136/jitc-2020-SITC2020.0363

20) Safety and efficacy of vactosertib, a TGF-βR1 kinase inhibitor, in combination with paclitaxel in patients with metastatic gastric adenocarcinoma. Annals of Oncology, September 2020. https://doi.org/10.1016/j.annonc.2020.08.1959

21) A Phase 1 study of TGF-β inhibitor, vactosertib, in combination with imatinib in patients with advanced desmoid tumor (aggressive fibromatosis). Journal of Clinical Oncology, May 2020. https://doi.org/10.1200/JCO.2020.38.15_suppl.11557

22) Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study. Investigational New Drugs, July 2019. https://doi.org/10.1007/s10637-019-00835-y

23) Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models. Scientific Reports, February 2020. https://doi.org/10.1038/s41598-020-59893-5

24) Integrated drug profiling and CRISPR screening identify essential pathways for CAR T-cell cytotoxicity. Blood, February 2020. https://doi.org/10.1182/blood.2019002121

25) Population pharmacokinetics of vactosertib, a new TGF-β receptor type Ι inhibitor, in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology, October 2019. https://doi.org/10.1007/s00280-019-03979-z

26) Combination therapy for treating advanced drug-resistant acute lymphoblastic leukemia. Cancer Immunology Research, July 2019. https://doi.org/10.1158/2326-6066.CIR-19-0058

27) Diagnostic and therapeutic methods for cancer. WO2019090263 A1

28) Association of TGF-β responsive signature with anti-tumor effect of vactosertib, a potent, oral TGF-β receptor type I (TGFBRI) inhibitor in patients with advanced solid tumors. Journal of Clinical Oncology, June 2018. https://doi.org/10.1200/JCO.2018.36.15_suppl.3031

29) Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-β signaling. Oncotarget, December 2016. http://doi.org/10.18632/oncotarget.13867

30) Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells. Cancer Science, February 2016. http://doi.org/10.1111/cas.12849

31) TIMP-1 mediates TGF-β-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling. Scientific Reports, November 2015. https://doi.org/10.1038/srep16492

32) Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells. Oncotarget, 2015 October. http://doi.org/10.18632/oncotarget.6063

33) EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. Molecular Cancer Therapeutics, July 2014. http://doi.org/10.1158/1535-7163.MCT-13-0903

34) Methods of treating fibrosis, cancer and vascular injuries. US8513222 B2 (2013)

Other indications

1) Hair growth stimulant with capable of activating dermal papilla cells at the root of hair. WO2022158571 A1

2) Large-scale RNAi screening uncovers therapeutic targets in the parasite Schistosoma mansoni. Science, September 2020. https://doi.org/10.1126/science.abb7699

3) Kaurenoic acid activates TGF-β signaling. Phytomedicine, August 2017. https://doi.org/10.1016/j.phymed.2017.04.008

4) Generation of PDGFRα+ cardioblasts from pluripotent stem cells. Scientific Reports, February 2017. https://doi.org/10.1038/srep41840

5) Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation. Nature Communications, July 2015. https://doi.org/10.1038/ncomms8600

EW-8198

Non-alcoholic steatohepatitis (NASH)

1) Discovery of (E)-3-(3-((2-cyano-4'-dimethylaminobiphenyl-4-ylmethyl)-cyclohexanecarbonylamino)-5-fluorophenyl)acrylic acid methyl ester, an intestine-specific, FXR partial agonist for the treatment of nonalcoholic steatohepatitis. Journal of Medicinal Chemistry, July 2022. https://doi.org/10.1021/acs.jmedchem.2c00641

2) Intestine-specific partial agonists of farnesoid X receptor and uses thereof. US63/356261 (2022)