Targeting the TGF-β signaling pathway for fibrosis therapy: a patent review (2015–2020)

References

• Distler JHW, Györfi AH, Ramanujam M, et al. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol. 2019 Dec; 15(12):705–730. eng. PubMed PMID: 31712723.
   PubMed Web of Science ®Google Scholar
• Zhao X, Kwan JYY, Yip K, et al. Targeting metabolic dysregulation for fibrosis therapy. Nat Rev Drug Discov. 2020 Jan; 19(1):57–75. PubMed PMID: 31548636; eng.
   PubMed Web of Science ®Google Scholar
• Rockey DC, Bell PD, Hill JA. Fibrosis–a common pathway to organ injury and failure. N Engl J Med. 2015 Mar 19; 372(12):1138–1149. PubMed PMID: 25785971; eng.
   PubMed Web of Science ®Google Scholar
• Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity. 2019 Apr 16; 50(4):992–1006. PubMed PMID: 30995511; eng.
   PubMed Web of Science ®Google Scholar
• Bradding P, Pejler G. The controversial role of mast cells in fibrosis. Immunol Rev. 2018 Mar; 282(1):198–231. PubMed PMID: 29431218; eng.
   PubMed Web of Science ®Google Scholar
• Frangogiannis NG. Cardiac fibrosis: cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med. 2019 Feb; 65:70–99. PubMed PMID: 30056242; eng.
   PubMed Web of Science ®Google Scholar
• Györfi AH, Matei AE, Distler JHW. Targeting TGF-β signaling for the treatment of fibrosis. Matrix biology. Journal of the International Society for Matrix Biology. 2018 Aug; 68-69:8–27. PubMed PMID: 29355590; eng.
   PubMed Web of Science ®Google Scholar
• Lodyga M, Hinz B. TGF-β1 - A truly transforming growth factor in fibrosis and immunity. Semin Cell Dev Biol. 2020 May; 101:123–139. PubMed PMID: 31879265; eng.
   PubMed Web of Science ®Google Scholar
• Bonafoux D, Lee WC. Strategies for TGF-beta modulation: a review of recent patents. Expert Opin Ther Pat. 2009 Dec; 19(12):1759–1769. PubMed PMID: 19939191; eng.
   PubMed Web of Science ®Google Scholar
• Rosenbloom J, Macarak E, Piera-Velazquez S, et al. Human fibrotic diseases: current challenges in fibrosis research. Methods Mol Biol. 2017;1627:1–23. PubMed PMID: 28836191; eng.
   PubMedGoogle Scholar
• Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016 Jun; 12(6):325–338. PubMed PMID: 27108839; eng.
   PubMed Web of Science ®Google Scholar
• Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther. 1999 Oct; 291(1):367–373. PubMed PMID: 10490926; eng.
   PubMed Web of Science ®Google Scholar
• Antoniou KM, Wuyts W, Wijsenbeek M, et al. Medical therapy in idiopathic pulmonary fibrosis. Semin Respir Crit Care Med. 2016 Jun; 37(3):368–377. PubMed PMID: 27231861; eng.
   PubMed Web of Science ®Google Scholar
• Miyazawa K, Miyazono K. Regulation of TGF-β family signaling by inhibitory smads. Cold Spring Harb Perspect Biol. 2017 Mar 1; 9(3): PubMed PMID: 27920040; PubMed Central PMCID: PMCPMC5334261. eng. DOI:10.1101/cshperspect.a022095
   PubMed Web of Science ®Google Scholar
• Fabregat I, Moreno-Càceres J, Sánchez A, et al. TGF-β signalling and liver disease. Febs J. 2016 Jun; 283(12):2219–2232. PubMed PMID: 26807763; eng.
   PubMed Web of Science ®Google Scholar
• Klinkhammer BM, Floege J, Boor P. PDGF in organ fibrosis. Mol Aspects Med. 2018 Aug; 62:44–62. PubMed PMID: 29155002; eng.
   PubMed Web of Science ®Google Scholar
• Papadopoulos N, The LJ. PDGF/PDGFR pathway as a drug target. Mol Aspects Med. 2018 Aug; 62:75–88. PubMed PMID: 29137923; eng.
   PubMed Web of Science ®Google Scholar
• Yan Z, Kui Z, Ping Z. Reviews and prospectives of signaling pathway analysis in idiopathic pulmonary fibrosis. Autoimmun Rev. 2014 Oct; 13(10):1020–1025. PubMed PMID: 25182202; eng.
   PubMed Web of Science ®Google Scholar
• Huang XL, Wang YJ, Yan JW, et al. Role of anti-inflammatory cytokines IL-4 and IL-13 in systemic sclerosis. Inflammation Res. 2015 Apr; 64(3–4):151–159. PubMed PMID: 25725697; eng.
   PubMed Web of Science ®Google Scholar
• Chen R, Sun Y, Cui X, et al. Autophagy promotes aortic adventitial fibrosis via the IL-6/Jak1 signaling pathway in Takayasu’s arteritis. J Autoimmun. 2019 May; 99:39–47. PubMed PMID: 30765261; eng.
   PubMed Web of Science ®Google Scholar
• Ahmed S, Misra DP, Agarwal V. Interleukin-17 pathways in systemic sclerosis-associated fibrosis. Rheumatol Int. 2019 Jul; 39(7):1135–1143. PubMed PMID: 31073660; eng.
   PubMed Web of Science ®Google Scholar
• Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000 May 4; 342(18):1350–1358. PubMed PMID: 10793168.
   PubMed Web of Science ®Google Scholar
• Reed NI, Tang YZ, McIntosh J, et al. Exploring N-Arylsulfonyl-l-proline scaffold as a platform for potent and selective alphavbeta1 integrin inhibitors. ACS Med Chem Lett. 2016 Oct 13; 7(10):902–907. PubMed PMID: 27774126; PubMed Central PMCID: PMCPMC5066160.
   PubMed Web of Science ®Google Scholar
• Margadant C, Sonnenberg A. Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 2010 Feb; 11(2):97–105. PubMed PMID: 20075988; PubMed Central PMCID: PMCPMC2828749.
   PubMed Web of Science ®Google Scholar
• Millard M, Odde S, Neamati N. Integrin targeted therapeutics. Theranostics. 2011 Feb 17; 1:154–188. PubMed PMID: 21547158; PubMed Central PMCID: PMCPMC3086618.
   PubMed Web of Science ®Google Scholar
• Henderson NC, Sheppard D. Integrin-mediated regulation of TGFbeta in fibrosis. Biochim Biophys Acta. 2013 Jul; 1832(7):891–896. PubMed PMID: 23046811; PubMed Central PMCID: PMCPMC3573259.
   PubMed Web of Science ®Google Scholar
• Huang XZ, Wu JF, Cass D, et al. Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J Cell Biol. 1996 May; 133(4):921–928. PubMed PMID: 8666675; PubMed Central PMCID: PMCPMC2120829.
   PubMed Web of Science ®Google Scholar
• Prakash J, inventor; Integrin binding peptides and uses thereof patent WO2017069627. 2017.
   Google Scholar
• Kessler H, Kapp T, Reichart F, et al., inventors; Ligands for integrin avb8, synthesis and uses thereof patent WO2018167295. 2018.
   Google Scholar
• Tang Y, Sutcliffe JL, inventors; Alpha(v)beta(6) integrin-binding peptides and methods of use thereof patent WO2020051549. 2020.
   Google Scholar
• Degrado WF, Sheppard D, Jo H, et al., inventors; Anti-alphavbeta1 integrin compounds and methods patent WO2015048819. 2015.
   Google Scholar
• Coller BS, Filizola M, Foley MA, inventors; Tetrahydronaphthyridinepentanamide integrin antagonists patent WO2018009501. 2018.
   Google Scholar
• Ruminski PG, Griggs DW, Seiwert S, inventors; Integrin antagonists patent WO2018132268. 2018.
   Google Scholar
• Ruminski PG, Griggs DW, Seiwert S, inventors; Alphavbeta1 Integrin antagonists patent WO2020009889. 2020.
   Google Scholar
• Furuya T, Askew BC, inventors; Nonanoic and decanoic acid derivatives and uses thereof patent US2019040073. 2019.
   Google Scholar
• Furuya T, Askew BC inventors; Fluorinated tetrahydronaphthyridinyl nonanoic acid derivatives and uses thereof patent WO2016134223. 2016.
   Google Scholar
• MAi A, inventor Integrin antagonists patent WO2020033724. 2020.
   Google Scholar
• Shechter S, Zomer E, Traber PG, et al., inventors; Selenogalactoside compounds for the prevention and treatment of diseases associated with galectin and the use thereof patent WO2017152048. 2017.
   Google Scholar
• Ruminski PG, Griggs DW, inventors; Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists patent WO2017117538. 2017.
   Google Scholar
• Devasthale P, Wang W, inventors; Azole amides and amines as alpha v integrin inhibitors patent WO2018089358. 2018.
   Google Scholar
• Zhao G, Mignone J, inventors; Pyrrole amides as alpha v integrin inhibitors patent WO2018089360. 2018.
   Google Scholar
• Zhao G, Mignone J, inventors; Pyrrolopyrazine derivatives as alpha V integrin inhibitors patent WO2019094319. 2019.
   Google Scholar
• Jiang L, Morgans DJ, Bergne G, et al. inventors; N-Acyl amino acid compounds and methods of use patent WO2018049068. 2018.
   Google Scholar
• Morgans DJJ, Halcomb RL, Bergnes G, et al. inventors; Amino acid compounds and methods of use patent WO2018119087. 2018.
   Google Scholar
• Leftheris K, Reilly M, Finkelstein D, et al., inventors; Amino acid compouds with unbranched linkers and methods of use patent WO2020006315. 2020.
   Google Scholar
• Kapp TG, Rechenmacher F, Neubauer S, et al. A comprehensive evaluation of the activity and selectivity profile of ligands for RGD-binding integrins. Sci Rep. 2017;7:39805.
   PubMed Web of Science ®Google Scholar
• Hatley RJD, Macdonald SJF, Slack RJ, et al. An alphav-RGD integrin inhibitor toolbox: drug discovery insight, challenges and opportunities. Angew Chem Int Ed Engl. 2018;57:3298–3321.
   PubMed Web of Science ®Google Scholar
• Nadrah K, Dolenc MS. Dual antagonists of integrins. Curr Med Chem. 2005;12:1449–1466.
   PubMed Web of Science ®Google Scholar
• Sulyok GA, Gibson C, Goodman SL, et al. Solid-phase synthesis of a nonpeptide RGD mimetic library: new selective alphavbeta3 integrin antagonists. J Med Chem. 2001;44:1938–1950.
   PubMed Web of Science ®Google Scholar
• Harrison BA, Bursavich MG, Brewer M, et al. inventors; Inhibitors of (alpha-v)(beta-6) integrin patent US2020157075. 2020.
   Google Scholar
• Harrison BA, Dowling JE, Gerasyuto AI, et al. inventors; Inhibiting alphavbeta6 integrin patent WO2020047239. 2020.
   Google Scholar
• Harrison BA, Dowling JE, Gerasyuto AI, et al. inventors, Inhibitors of alphavbeta6 integrin patent WO2020081154. 2020.
   Google Scholar
• Yokosaki Y, Nishimichi N, inventors; Anti-integrin alpha11 monoclonal antibody and use thereof patent WO2019168176. 2019.
   Google Scholar
• Wang R, Zhu J, Dong X, et al. GARP regulates the bioavailability and activation of TGFbeta. Mol Biol Cell. 2012 Mar; 23(6):1129–1139. PubMed PMID: 22278742; PubMed Central PMCID: PMCPMC3302739.
   PubMed Web of Science ®Google Scholar
• Saunders M, Coulie P, Lucas S, et al., inventors; Anti-GARP protein and uses thereof patent WO2016125017. 2016.
   Google Scholar
• Van Der Woning S, Borgions F, Dreier T, et al., inventors; GARP-TGF-beta antibodies patent WO2018206790. 2018.
   Google Scholar
• Schurpf T, Datta A, Carven GJ, et al., inventors; Isoform-specific, context-permissive TGFbeta1 inhibitors and use thereof patent WO2018129329. 2018.
   Google Scholar
• Schurpf T, Littlefield C, Carven GJ, et al., inventors; LTBP complex-specific inhibitors of TGF-beta1 and uses thereof patent WO2019023661. 2019.
   Google Scholar
• Datta A, Capili A, Schurpf T, et al., inventors; High-affinity, isoform-selective TGFbeta1 inhibitors and use thereof patent WO2020014460. 2020.
   Google Scholar
• Datta A, Schurpf T, Capili A, et al., inventors; TGFbeta1 inhibitors and use thereof patent WO2020014473. 2020.
   Google Scholar
• Kanamori M, inventor; Cross-species anti-latent TGF-beta 1 antibodies and methods of use patent WO2019163927. 2019.
   Google Scholar
• Jia C, Cui X, Ou T, inventors; A shRNA, carrier, kit for knockdown TGF-beta1 and application thereof patent CN109055377. 2018.
   Google Scholar
• Kuroda M, Gabazza E, Kobayashi T, et al., inventors; Single-stranded nucleic acid molecule for controlling expression of TGF-beta1 gene patent WO2015093495. 2015.
   Google Scholar
• Matsumoto T, Toyofuku H, inventors; Single-stranded nucleic acid molecule for inhibiting TGF-beta1 expression patent WO2016098782. 2016.
   Google Scholar
• Yamada T, Toyofuku H, Tahara K, et al. inventors; Composition stably containing single-stranded nucleic acid molecule that suppresses expression of TGF-beta1 gene patent WO2017073767. 2017.
   Google Scholar
• Zhou J, Li Q, Xu J, et al. inventors; Pharmaceutical compositions and methods of use for activation of human fibroblast and myofibroblast apoptosis patent WO2018081726. 2018.
   Google Scholar
• Zhang P, Lu X, Evans DM, et al. inventors; Targeted delivery of therapeutic molecules patent WO2020139788. 2020.
   Google Scholar
• Jenkins G. The role of proteases in transforming growth factor-beta activation. Int J Biochem Cell Biol. 2008; 40(6–7):1068–1078. . PubMed PMID: 18243766.
   PubMed Web of Science ®Google Scholar
• Dai R, Liu X, Deng Y, et al., inventors; A falling-carbon sesquiterpene compound in preparing anti-liver fibrosis medicine application patent CN107753493. 2018.
   Google Scholar
• Dai R, Liu X, Deng Y, et al., inventors; Aryl naphthalene type lignan compound in preparing anti-liver fibrosis medicine patent CN110538176. 2019.
   Google Scholar
• Delgado Mora M, Campos Salinas J, inventors; Cortistatin or an analogue thereof as a pharmaceutically active agent in latent form patent WO2020165457. 2020.
   Google Scholar
• Qiu H, Pan C, Bird J, inventors; ScFv-Fc dimers that bind trasforming growth factor-beta1 with high affinity, avidity and specificity patent WO2016141244. 2016.
   Google Scholar
• Bon H, Compson JE, Dixon KL, et al. inventors; Antagonist antibodies that t bind to human TGFbeta1, TGFbeta2 and to TGFbeta3 and their use for the treatment of lung fibrosis patent WO2017211873. 2017.
   Google Scholar
• Ibebunjo C, Jacobi C, Meyer A, et al. inventors; TGFbeta 2 antibodies patent WO2017141208. 2017.
   Google Scholar
• Kumar R, Grinberg A, Sako DS, et al., inventors; TGF-beta receptor type II variants and uses thereof patent US2018179261. 2018.
   Google Scholar
• Ritter G, Dunn S, inventors; Humanized and variant TGF-beta1 specific antibodies and methods and uses thereof patent WO2020095113. 2020.
   Google Scholar
• Ritter G, Dunn S, inventors; Humanized and variant TGF-beta3 specific antibodies and methods and uses thereof patent WO2020095104. 2020.
   Google Scholar
• Derynck R, Turley SJ, Akhurst RJ. TGFbeta biology in cancer progression and immunotherapy. Nat Rev Clin Oncol. 2021 Jan; 18(1):9–34. PubMed PMID: 32710082.
   PubMed Web of Science ®Google Scholar
• Targeting IY. TGF-beta signaling in kidney fibrosis. Int J Mol Sci. 2018 Aug 27; 19(9): PubMed PMID: 30150520; PubMed Central PMCID: PMCPMC6165001. DOI:10.3390/ijms19092532
   Web of Science ®Google Scholar
• Varricchio L, Mascarenhas J, Migliaccio AR, et al. AVID200, a potent trap for TGF-β ligands inhibits TGF-β1 signaling in human myelofibrosis. Blood. 2018;132(Supplement 1):1791.
   Google Scholar
• Yu P, Grinberg A, Sako DS, et al., inventors, inventor Compositions and methods for treating pulmonary hypertension patent EP368584A1. 2020.
   Google Scholar
• Zhang C, Yao C, Zhang H, et al., inventors Fusion protein of eta antibody and TGF-β trap and pharmaceutical composition and application thereof patent WO2021008519. 2021.
   Google Scholar
• Finnson KW, Almadani Y, Philip A. Non-canonical (non-SMAD2/3) TGF-β signaling in fibrosis: mechanisms and targets. Semin Cell Dev Biol. 2020;101:115–122.
   PubMed Web of Science ®Google Scholar
• Giannelli G, Santoro A, Kelley RK, et al. Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-βRI inhibitor galunisertib. PloS One. 2020;15(3):e0222259.
   PubMed Web of Science ®Google Scholar
• Wu X, He C, Ma H, et al., inventors; 4-(4-Pyrazole oxy) quinoline compound, preparation method thereof, pharmaceutical composition and application thereof patent CN11130313. 2020.
   Google Scholar
• Wu X, Ma H, Li M, et al., inventors; 2-4-(4-Pyrazol) pyridine compound, preparation method thereof, pharmaceutical composition and application thereof patent CN 11111656. 2020.
   Google Scholar
• Wang Y, Zhao L, Wang Y, et al., inventors; Compound as TGF-beta R1 inhibitor and application thereof patent CN 111072645. 2020.
   Google Scholar
• Wang Y, Zhao L, Wang Y, et al., inventors; TGF-betaR1 inhibitor and use thereof patent CN 111196804. 2020.
   Google Scholar
• Li G, Zheng H, Song Z, et al., inventors; Novel pyrazole derivative as ALK5 inhibitor and uses thereof patent CN 109415346. 2019.
   Google Scholar
• Chen L, Yang T, Lu DW, et al. Central role of dysregulation of TGF-beta/Smad in CKD progression and potential targets of its treatment. Biomed Pharmacother. 2018 May; 101:670–681. PubMed PMID: 29518614.
   PubMed Web of Science ®Google Scholar
• Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012 Oct; 13(10):616–630. PubMed PMID: 22992590; PubMed Central PMCID: PMCPMC4027049.
   PubMed Web of Science ®Google Scholar
• Eser PO, Janne PA. TGFbeta pathway inhibition in the treatment of non-small cell lung cancer. Pharmacol Ther. 2018 Apr; 184:112–130. PubMed PMID: 29129643.
   PubMed Web of Science ®Google Scholar
• Katz LH, Likhter M, Jogunoori W, et al. TGF-beta signaling in liver and gastrointestinal cancers. Cancer Lett. 2016 Sep 1; 379(2):166–172. PubMed PMID: 27039259; PubMed Central PMCID: PMCPMC5107316.
   PubMed Web of Science ®Google Scholar
• Park KK, Kim JY, Lee WR, et al. inventors; A novel synthetic oligodeoxynucleotides that inhibit DNA and RNA simultaneously and pharmaceutical composition for the prevention and treatment of fibrosis patent CN105802967. 2016.
   Google Scholar
• Wang X, Yang J, Fan J, et al. inventors; A method for constructing PROTAC double-target and use thereof patent WO2020119192. 2020.
   Google Scholar
• Shukla MN, Rose JL, Ray R, et al. Hepatocyte growth factor inhibits epithelial to myofibroblast transition in lung cells via Smad7. Am J Respir Cell Mol Biol. 2009 Jun; 40(6):643–653. PubMed PMID: 18988920; PubMed Central PMCID: PMCPMC2689916.
   PubMed Web of Science ®Google Scholar
• A-m D, Ahmed M, Pulz RA, et al. inventors; Carboxamide derivatives patent WO2015175796. 2015.
   Google Scholar
• A-m D, Ahmed M, Pulz RA, et al. inventors; Carboxamide derivatives patent WO2015177646. 2015.
   Google Scholar
• Edwards A, Ahmed M, Pulz RA, et al. inventors; Carboxamide derivatives patent US9403833. 2016.
   Google Scholar
• Bala KJ, Brearley A, Dale J, et al. inventors; Carboxamide derivatives patent US2019381011. 2019.
   Google Scholar
• Petrash M, Wang X-J, inventors; Smad7 for treatment and prevention of posterior capsule opacification patent WO2019133950. 2019.
   Google Scholar
• Schuster S, Feldstein AE. NASH: novel therapeutic strategies targeting ASK1 in NASH. Nat Rev Gastroenterol Hepatol. 2017; 14(6):329–330. . PubMed PMID: 28377639; eng.
   PubMed Web of Science ®Google Scholar
• Sakauchi C, Wakatsuki H, Ichijo H, et al. Pleiotropic properties of ASK1. Biochim Biophys Acta Gen Subj. 2017;1861(1 Pt A):3030–3038. PubMed PMID: 27693599; eng.
   PubMed Web of Science ®Google Scholar
• Hayakawa R, Hayakawa T, Takeda K, et al. Therapeutic targets in the ASK1-dependent stress signaling pathways. Proc Jpn Acad, Ser B, Phys Biol Sci. 2012; 88(8):434–453. PubMed PMID: 23060232; eng.
   PubMed Web of Science ®Google Scholar
• Kim EK, Choi E-J. Compromised MAPK signaling in human diseases: an update. Arch Toxicol. 2015; 89(6):867–882. . PubMed PMID: 25690731; eng.
   PubMed Web of Science ®Google Scholar
• Nishida T, Hattori K, Watanabe K. The regulatory and signaling mechanisms of the ASK family. Adv Biol Regul. 2017; 66. PubMed PMID: 28669716; eng. DOI:10.1016/j.jbior.2017.05.004
   PubMedGoogle Scholar
• Wang T, Liu B, inventors; ASK1 inhibitor and application thereof patent CN110698471A. 2020–01–17.
   Google Scholar
• Wang T, inventors; A new ASK1 inhibitor and application thereof patent CN110294746A. 2019–10–01.
   Google Scholar
• Liu B, inventors; Tricyclic ring ask1 inhibitors and use thereof patent WO2020063727. 2020.
   Google Scholar
• Zhang C, Wang C, Han X, et al. Inventors; Apoptosis signal regulating kinase inhibitor and application thereof patent CN111018831A. 2020–04–17.
   Google Scholar
• Kim D, Yoo J, Ji S KJ-H, et al., inventors; Novel (isopropyl-triazolyl)pyridinyl-substituted benzooxazinone or benzothiazinone derivatives and use thereof patent WO2020080742. 2020.
   Google Scholar
• Kim D, Yoo J, Ji S, et al.,inventors; Novel n-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives and use thereof patent WO2020080741. 2020.
   Google Scholar
• Smith CR inventor; Ask1 isoindolin-1-one inhibitors and methods of use thereof patent WO2020006429. 2020.
   Google Scholar
• Notte G, inventor; Apoptosis signal-regulating kinase inhibitor patent US20190248762. 2019.
   Google Scholar
• Notte G, inventor; Apoptosis signal-regulating kinase inhibitors patent US 20180303844. 2018.
   Google Scholar
• Wang Y, Li H, inventors; 1, 2, 4-triazole compound patent WO2019072130. 2019.
   Google Scholar
• S D B, inventor; ASK1 inhibitor compounds and uses thereof patent WO2019136025. 2019.
   Google Scholar
• Brown SD, inventors; ASK1 inhibitor compounds and uses thereof patent CN110730661A. 2020–01–24.
   Google Scholar
• Yang X, Pan S, Ma F, et al. inventors; Fused bicyclic compounds and uses thereof in medicine patent CN109400625A. 2019.
   Google Scholar
• Yang X, Ma F, Zhang Y, et al., inventors; Amide derivative and use thereof in medicine patent WO2018090869. 2018.
   Google Scholar
• Wang Y, Zhao L, Ge C, et al. inventors; Heterocyclic compound acting as ASK inhibitor and use thereof patent CN109456308A. 2019.
   Google Scholar
• Amantini D, Mesic M, Saxty G, et al. inventors; ASK1 inhibiting pyrrolopyrimidine and pyrrolopyridine derivatives patent CN111094283A. 2020.
   Google Scholar
• Rowbottom MW, inventors; Apoptosis signal-regulating kinase 1 (ask 1) inhibitor compounds patent US20200048218. 2020.
   Google Scholar
• Rowbottom MW, Hutchinson JH inventor; Apoptosis signal-regulating kinase 1 (ask 1) inhibitor compounds patent WO2019070742. 2019.
   Google Scholar
• Rowbottom MW inventor; Apoptosis signal-regulating kinase 1 (ask 1) inhibitor compounds patent WO2019099703. 2019.
   Google Scholar
• Zhang J, Chen Y, Li B, et al., inventor; Inhibitor of apoptosis signal-regulating kinase-1 and application thereof patent WO2019134680. 2019.
   Google Scholar
• Xu X, inventor; Urea derivatives as inhibitors of ask1 patent WO2019099307. 2019.
   Google Scholar
• Xu X, inventor; Oxazole and thiazole derivatives as inhibitors of ask1 patent WO2019099203. 2019.
   Google Scholar
• Jin B, Hung G, inventor; Apoptosis signal-regulating kinase inhibitors and uses thereof patent WO2019051265. 2019.
   Google Scholar
• Jin B, Hung G, inventor; Pyridinyl based apoptosis signal-regulation kinase inhibitors patent WO2018151830. 2018.
   Google Scholar
• Lei H, Liu G, Tian Y, et al., inventors; Isoquinolin and naphthydrin compounds patent WO2018160406. 2018.
   Google Scholar
• Liu G, Yu H, Tang J, et al., inventors; Kinase inhibitor and preparation method therefor and use thereof patent WO2018149284. 2018.
   Google Scholar
• Gao P, Sun G, Wang S, et al., inventors; Amide derivative inhibitor and preparation method and application thereof patent WO2018157856. 2018.
   Google Scholar
• Cai S, Du Z, Kim M, et al., inventors; Phosphatidylinositol 3-kinase inhibitors patent US20150361068. 2015.
   Google Scholar
• Biagetti M, Capelli AM, Guala M, inventors; Pyridazinone derivatives as phosphoinositide 3-kinases inhibitors patent WO2016038140. 2016.
   Google Scholar
• Hirsch E, Ghico A, inventor; Novel PI3K GAMMA inhibitor peptide for treatment of respiratory system diseases patent WO2016103176. 2016.
   Google Scholar
• Low P, Hettiarachchi SU, Li Y-H, et al., inventors; Fibroblast activation protein (fap) targeted imaging and therapy in fibrosis patent WO2020081522. 2020.
   Google Scholar
• Bradner JE, Qi J, Tanak M, inventors; Diaminopyrimidine benzenesulfone derivatives and uses thereof patent US20190135790. 2019.
   Google Scholar
• Sassmann-Schweda A, Singh P, Tang C, et al. Increased apoptosis and browning of TAK1-deficient adipocytes protects against obesity. JCI Insight. 2016;1(7):e81175. PubMed PMID: 27699262; eng.
   PubMed Web of Science ®Google Scholar
• Van Caam A, Madej W, Garcia De Vinuesa A, et al. TGFβ1-induced SMAD2/3 and SMAD1/5 phosphorylation are both ALK5-kinase-dependent in primary chondrocytes and mediated by TAK1 kinase activity. Arthritis Res Ther. 2017;19(1):112. PubMed PMID: 28569204; eng.
   PubMedGoogle Scholar
• Li L, Huang B, Song S, et al. A20 functions as mediator in TNFα-induced injury of human umbilical vein endothelial cells through TAK1-dependent MAPK/eNOS pathway. Oncotarget. 2017;8(39):65230–65239. PubMed PMID: 29029426; eng.
   PubMedGoogle Scholar
• Takahashi E, Haga A, Tanihara H. Merlin regulates epithelial-to-mesenchymal transition of ARPE-19 cells via TAK1-p38MAPK-Mediated activation. Invest Ophthalmol Vis Sci. 2015; 56(4):2449–2458. . PubMed PMID: 25783601; eng.
   PubMed Web of Science ®Google Scholar
• Mao Z-M, Wan Y-G, Sun W, et al. [Effects and mechanisms of huangkui capsule ameliorating renal fibrosis in diabetic nephropathy rats via inhibiting oxidative stress and p38MAPK signaling pathway activity in kidney]. Zhongguo Zhong Yao Za Zhi. 2014; 39(21):4110–4117. PubMed PMID: 25775777; chi.
   PubMedGoogle Scholar
• Ma X, Wang C, Liu X, et al. inventors; Heterocyclic pyrimidine compounds, compositions and methods of treating pulmonary fibrosis disease patent CN109806262A. 2019.
   Google Scholar
• Tweardy DJ, Kasembeli MM, Xu XM, et al., inventors; Methods and compositions for treatment of fibrosis patent US20150051233. 2015.
   Google Scholar
• Lindholm EM, Schmidt S, inventors; Antisense oligonucleotides targeting stat1 patent WO2020007889. 2020.
   Google Scholar
• Holtzman M, Gerovac B, Han Z, et al., inventors; Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof patent WO2019232275. 2019.
   Google Scholar
• Lander C, Brophy C, Patterson C, inventors; Inhibition of cardiac fibrosis in myocardial infarction patent US20200172574. 2020.
   Google Scholar
• Roger VL, Go AS, Lloyd-Jones DM, et al. Executive summary: heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125(1):188–197. PubMed PMID: 22215894; eng.
   PubMed Web of Science ®Google Scholar
• Muto A, Panitch A, Kim N, et al. Inhibition of mitogen activated protein kinase activated protein kinase II with MMI-0100 reduces intimal hyperplasia ex vivo and in vivo. Vascul Pharmacol. 2012;56(1–2):47–55. PubMed PMID: 22024359; eng.
   PubMed Web of Science ®Google Scholar
• Vittal R, Fisher A, Gu H, et al. Peptide-mediated inhibition of mitogen-activated protein kinase-activated protein kinase-2 ameliorates bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2013;49(1):47–57. PubMed PMID: 23470623; eng.
   PubMed Web of Science ®Google Scholar
• Ward BC, Kavalukas S, Brugnano J, et al. Peptide inhibitors of MK2 show promise for inhibition of abdominal adhesions. J Surg Res. 2011;169(1):e27–e36. PubMed PMID: 21492875; eng.
   PubMed Web of Science ®Google Scholar
• Beauchamps MG, Hilgraf R, Kothare MA, et al., inventors; Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use patent US2020078359. 2020.
   Google Scholar
• He W, Shi F, Zhou Z-W, et al. A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver. Drug Des Devel Ther. 2015;9:3989–4104. PubMed PMID: 26347199; eng.
   PubMed Web of Science ®Google Scholar
• Shaul YD, The SR. MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2007; 1773(8):1213–1226. PubMed PMID: 17112607; eng.
   PubMed Web of Science ®Google Scholar
• Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017; 169(3):381–405. . PubMed PMID: 28431241; eng.
   PubMed Web of Science ®Google Scholar
• Chen J, Somanath PR, Razorenova O, et al. Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat Med. 2005; 11(11):1188–1196. PubMed PMID: 16227992; eng.
   PubMed Web of Science ®Google Scholar
• Somanath PR, Chen J, Byzova TV. Akt1 is necessary for the vascular maturation and angiogenesis during cutaneous wound healing. Angiogenesis. 2008; 11(3):277–288. . PubMed PMID: 18415691; eng.
   PubMed Web of Science ®Google Scholar
• Abdalla M, Goc A, Segar L, et al. Akt1 mediates α-smooth muscle actin expression and myofibroblast differentiation via myocardin and serum response factor. J Biol Chem. 2013;288(46):33483–33493. PubMed PMID: 24106278; eng.
   PubMed Web of Science ®Google Scholar
• Hinz B, Phan SH, Thannickal VJ, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012;180(4):1340–1355. PubMed PMID: 22387320; eng.
   PubMed Web of Science ®Google Scholar
• Altenhöfer S, Radermacher KA, Kleikers PW, et al. Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid Redox Signal. 2015;23(5):406–427.
   PubMed Web of Science ®Google Scholar
• Liu R-M, Desai LP. Reciprocal regulation of TGF-β and reactive oxygen species: a perverse cycle for fibrosis. Redox Biol. 2015;6:565–577.
   PubMed Web of Science ®Google Scholar
• Liu RM, Desai LP. Reciprocal regulation of TGF-beta and reactive oxygen species: a perverse cycle for fibrosis. Redox Biol. 2015 Dec; 6:565–577. PubMed PMID: 26496488; PubMed Central PMCID: PMCPMC4625010.
   PubMed Web of Science ®Google Scholar
• Machin P, Chambers M, Hodges A, et al., inventors, inventor Novel compounds as NADPH oxidase inhibitors patent WO202065048. 2020.
   Google Scholar
• Kumar S, Chaudhari SS, Gharat LA, et al., inventors; Substituted bicyclic heterocyclic compounds as NADPH oxidase inhibitors patent WO 2018203298. 2018.
   Google Scholar
• Jacintho JD, Clark RC, Sheng T, et al., inventors; Arylcarboxamides and uses thereof patent WO 2017192304. 2017.
   Google Scholar
• Wikstrӧm P, Walum E, Wilcke M, inventors; Compounds for use in the treatment of conditions associated with NADPH oxidase patent WO 2016096720. 2016.
   Google Scholar
• Wikstrӧm P, Walum E, Wilcke M, inventors; N2-(3,4-dimethylphenyl)-6-((4-(P-tolyl)piperazin-1-yl)methyl)-1,3,5-trizine-2,4-diamine patent WO 2016133446. 2016.
   Google Scholar
• Aissaoui H, Bolli M, Boss C, et al., inventors; NADPH oxidase 4 inhibitors. 2016.
   Google Scholar
• Kim SK, Barron L, Hinck CS, et al. An engineered transforming growth factor beta (TGF-beta) monomer that functions as a dominant negative to block TGF-beta signaling. J Biol Chem. 2017 Apr 28; 292(17):7173–7188. PubMed PMID: 28228478; PubMed Central PMCID: PMCPMC5409485.
   PubMed Web of Science ®Google Scholar