612
Views
16
CrossRef citations to date
0
Altmetric
Review

Small molecule agonists of toll-like receptors 7 and 8: a patent review 2014 – 2020

, , &
Pages 825-845 | Received 29 Jun 2020, Accepted 15 Sep 2020, Published online: 14 Oct 2020

References

  • Krieg AM, Vollmer J. Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol Rev. 2007 Dec;220:251–269.
  • Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006 Feb 24;124(4):783–801.
  • Kawai T, Akira S. Pathogen recognition with Toll-like receptors. Curr Opin Immunol. 2005 Aug;17(4):338–344.
  • Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–376.
  • Kumar H, Kawai T, Akira S. Toll-like receptors and innate immunity. Biochem Biophys Res Commun. 2009 Oct 30;388(4):621–625.
  • Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010 May;11(5):373–384.
  • Chen N, Xia P, Li S, et al. RNA sensors of the innate immune system and their detection of pathogens. IUBMB Life. 2017 May;69(5):297–304.
  • Jimenez-Dalmaroni MJ, Gerswhin ME, Adamopoulos IE. The critical role of toll-like receptors–From microbial recognition to autoimmunity: A comprehensive review. Autoimmun Rev. 2016 Jan;15(1):1–8.
  • Hussein WM, Liu TY, Skwarczynski M, et al. Toll-like receptor agonists: a patent review (2011–2013). Expert Opin Ther Pat. 2014 Apr;24(4):453–470.
  • Petes C, Odoardi N, Gee K. The toll for trafficking: toll-like receptor 7 delivery to the endosome. Front Immunol. 2017;8:1075.
  • Cervantes JL, Weinerman B, Basole C, et al. TLR8: the forgotten relative revindicated. Cell Mol Immunol. 2012 Nov;9(6):434–438.
  • Wang J, Shao Y, Bennett TA, et al. The functional effects of physical interactions among Toll-like receptors 7, 8, and 9. J Biol Chem. 2006 Dec 8;281(49):37427–37434.
  • Barton GM, Kagan JC. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol. 2009 Aug;9(8):535–542.
  • Jung S, von Thulen T, Laukemper V, et al. A single naturally occurring 2ʹ-O-methylation converts a TLR7- and TLR8-activating RNA into a TLR8-specific ligand. PLoS One. 2015;10(3):e0120498.
  • Hoebe K, Janssen E, Beutler B. The interface between innate and adaptive immunity. Nat Immunol. 2004 Oct;5(10):971–974.
  • Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001 Aug;2(8):675–680.
  • Heinz LX, Lee J, Kapoor U, et al. TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature. 2020 May;581(7808):316–322.
  • Pelka K, Shibata T, Miyake K, et al. Nucleic acid-sensing TLRs and autoimmunity: novel insights from structural and cell biology. Immunol Rev. 2016;269:60–75.
  • Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity. 2010 Mar 26;32(3):305–315.
  • Medvedev AE. Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. J Interferon Cytokine Res. 2013 Sep;33(9):467–484.
  • Hennessy EJ, Parker AE, O’Neill LA. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov. 2010 Apr;9(4):293–307.
  • Miller RL, Gerster JF, Owens ML, et al. Imiquidmod applied topically: a novel immune response modifer and new class of drug. Int J Immunopharmacol. 1999;21:1–14.
  • Kaufman HL, Atkins MB, Subedi P, et al. The promise of Immuno-oncology: implications for defining the value of cancer treatment. J Immunother Cancer. 2019 May 17;7(1):129.
  • Chi H, Li C, Zhao FS, et al. Anti-tumor Activity of Toll-Like Receptor 7 Agonists. Front Pharmacol. 2017;8:304.
  • Huck BR, Kotzner L, Urbahns K. Small Molecules Drive Big Improvements in Immuno-Oncology Therapies. Angew Chem Int Ed Engl. 2018 Apr 9;57(16):4412–4428.
  • Basith S, Manavalan B, Lee G, et al. Toll-like receptor modulators: a patent review (2006–2010). Expert Opin Ther Pat. 2011 Jun;21(6):927–944.
  • Patra MC, Choi S. Recent progress in the development of Toll-like receptor (TLR) antagonists. Expert Opin Ther Pat. 2016 Jun;26(6):719–730.
  • Quesniaux VFJ, Ryffel B. Toll-like receptors: emerging targets of immunomodulation. Expert Opin Ther Pat. 2005;14(1):85–100.
  • Apros Therapeutics, Inc. Pyrimidine compounds containing acidic groups. WO2018106606. 2018.
  • Korolowizc KE, Bin L, Huang X, et al. Liver-Targeted Toll-like receptor 7 agonist combined with entecavir promotes a functional cure in the woodchuck model of hepatitis B virus. Hepatol Commun. 2019;3(10):1296–1310.
  • Apros Therapeutics, Inc. Pyrimidine compounds containing acidic groups useful to treat diseases connected to the modulation of tlr7. WO2019236496. 2019.
  • Apros Therapeutics, Inc. Tlr7 peptide conjugates. WO2019236469. 2019.
  • Biontech AG. Substituted imidazoquinolines. WO2019048036. 2019.
  • Biontech AG Substituted imidazoquinolines as agonists of TLR7. WO2019048353. 2019.
  • Birdie Biopharmaceuticals, Inc. 2-Amino-quinoline derivatives. WO2018196823. 2018.
  • Bolt Biotherapeutics. Immunoconjugate synthesis method. WO2018009916. 2018.
  • Bolt Biotherapeutics. CL264 - conjugation to terminal carboxylic acid. WO2018112108. 2018.
  • Bolt Biotherapeutics. Immunoconjugate synthesis method −1. WO2018191746. 2018.
  • Bristol-Myers Squibb Company. 6-Amino-7,9-dihydro-8H-purin-8-one derivatives as toll-like receptor 7 (TLR7) agonists as immunostimulants. WO2019035968. 2019.
  • Bristol-Myers Squibb Company. Toll-like receptor 7 (TLR7) agonists having a tricyclic moiety, conjugates thereof, and methods and uses therefor. WO2019035969. 2019.
  • Bristol-Myers Squibb Company. 6-Amino-7,9-dihydro-8H-purin-8-one derivatives as immunostimulant toll-like receptor 7 (TLR7) agonists −1. WO2019035970. 2019.
  • Bristol-Myers Squibb Company. 6-amino-7,9-dihydro-8H-purin-8-one derivatives as immunostimulant toll-like receptor 7 (TLR7) agonists −2. WO2019035971. 2019.
  • Bristol-Myers Squibb Company. 6-Amino-7,9-dihydro-8h-purin-8-one derivatives as immunostimulant toll-like receptor 7 (TLR7) agonists. WO2019036023. 2019.
  • Bristol-Myers Squibb Company. Macrocyclic toll-like receptor 7 (TLR7) agonists. WO2019209811. 2019.
  • Bristol-Myers Squibb Company. 1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists and methods and uses therefor. WO2020028608. 2020.
  • Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Pyrrolopyrimidine compounds used as TLR7 agonist. WO2016023511. 2016.
  • Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Tlr7 agonist and pharmaceutical combination thereof for treating lung cancer. WO2019223788. 2019.
  • Chia Tai Tianqing Pharmaceutical Group Co., Ltd. 7-(thiazol-5-yl) pyrrolopyrimidine compound as tlr7 agonist. WO2017076346. 2017.
  • Centre National De La Recherche Scientifique. 1,2,4-triazine derivatives for the treatment of viral infections. WO2014053516. 2014.
  • Dynavax Technologies Corporation. Alkyl chain modified imidazoquinoline TLR7/8 agonist compounds and uses thereof. WO2019040491. 2019.
  • Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-D]pyrimidine compounds. WO2016141092. 2016.
  • Mackman RL, Mish M, Chin G, et al. Discovery of GS-9688 (Selgantolimod) as a potent and selective oral toll-like receptor 8 agonist for the treatment of chronic Hepatitis B. J Med Chem. 2020 May 14. DOI:10.1021/acs.jmedchem.0c00100
  • Gilead Sciences, Inc. Toll like receptor modulator compounds. WO2018045144. 2018.
  • Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine derivatives as toll like receptor modulators. WO2018045150. 2018.
  • Glaxosmithkline Biologicals Sa. Adenine derivatives which are useful in the treatment of allergic diseases or other inflammatory conditions. WO2016075661. 2016.
  • Glaxosmithkline Biologicals Sa. Compositions and uses. WO2016142880. 2016.
  • Shenzhen University. Novel small molecule immune agonists and immune targeting compounds and application thereof. WO2019192454. 2019.
  • Glaxosmithkline Biologicals S.A. Pegylated imidazoquinolines as TLR7 and TLR8 agonists. WO2017102652. 2017.
  • Glaxosmithkline Biologicals S.A. Imidazoquinoline derivatives and their use in therapy. WO2018046460. 2018.
  • Hoffman La Roche. Benzazepine dicarboxamide compounds with secondary amide function. WO2017202703. 2017.
  • Hoffman La Roche. Benzazepine dicarboxamide compounds with tertiary amide function. WO2017202704. 2017.
  • Hoffman La Roche 3-Substituted 5-amino-6H-thiazolo[4,5-D]pyrimidine-2,7-dione compounds for the treatment of prophylaxis of virus infection. WO2016091698. 2016.
  • Hoffman La Roche. Novel oxathiolane carboxylic acids and derivatives for the treatment and prophylaxis of virus infection. WO2016180691. 2016.
  • Hoffman La Roche. Novel substituted aminothiazolopyrimidinedione for the treatment and prophylaxis of virus infection. WO2016180743. 2016.
  • Hoffman La Roche. Novel substituted aminothiazolopyrimidinedione for the treatment and prophylaxis of virus infection patent WO2017001307. 2017.
  • Hoffman La Roche. 7-Substituted sulfonimidoylpurinone compounds for the treatment and prophylaxis of virus infection. WO2018041763. 2018.
  • Hoffman La Roche. Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor. WO2018050571. 2018.
  • Hoffman La Roche. Novel cyclicsulfonimidoylpurinone compounds and derivatives for the treatment and prophylaxis of virus infection. WO2018078149. 2018.
  • Hoffman La Roche. Novel sulfone compounds and derivatives for the treatment and prophylaxis of virus infection. WO2019155042. 2019.
  • Hoffman La Roche. 7-substituted sulfonimidoylpurinone compounds and derivatives for the treatment and prophylaxis of liver cancer. WO2019166432. 2019.
  • Janssen R&D Ireland. Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases. WO2014056953. 2014.
  • Janssen R&D Ireland. Thiene[3,2-d]pyrimidines derivatives for the treatment of viral infections. WO2015014815. 2015.
  • Janssen R&D Ireland. Macrocyclic purines for the treatment of viral infections. WO2014009509. 2014.
  • Janssen R&D Ireland. Macrocyclic deaza-purinones for the treatment of viral infections. WO2014154859. 2014.
  • Janssen R&D Ireland. Alkylpyrimidine derivatives for the treatment of viral infections and further diseases. WO2014023813. 2014.
  • Janssen R&D Ireland. Pyridone derivatives for the treatment of viral infections and further diseases. WO2014187932. 2014.
  • Janssen R&D Ireland. 2-Aminopyrimidine derivatives for the treatment of viral infections. WO2014128189. 2014.
  • Janssen Sciences Ireland Unlimited Company. 2,4-diaminoquinazoline derivatives and medical uses thereof. WO2019166532. 2019.
  • Janssen Sciences Ireland Uc. Dihydropyranopyrimidines for the treatment of viral infections. WO2018002319. 2018.
  • Jiangsu Hengrui Medicine Co. Heteroarothiadiazide-2,2-dioxide derivative, and preparation method therefor and application thereof in medicament. WO2018137614. 2018.
  • Jiangsu Hengrui Medicine Co. Heteroaryl-pyrazole derivative, and preparation method therefor and medical application thereof. WO2018210298. 2018.
  • Jiangsu Hengrui Medicine Co. Condensed heteroaryl derivatives, preparation method therefor, and application thereof in medicines. WO2019057158. 2019.
  • Jiangsu Hengrui Medicine Co. Condensed ring based ketone derivatives, preparation method thereof and application of derivatives in medicine. CN108794486. 2018.
  • Jiangsu Hengrui Medicine Co. Purinone derivative and preparation method thereof and application thereof in medicines. CN108948016. 2018.
  • Jiangsu Hengrui Medicine Co. Pyrazolo-heteroaryl derivative, preparation method and medical use thereof. WO2018095426. 2018.
  • Jiangsu Hengrui Medicine Co. Cyano-pyroolo-heteroaryl derivative, preparation method thereof and application of derivative to medicine. CN110317202. 2019.
  • Livo Shanghai Pharmaceutical Co LTD. Nitrogen-containing heterocyclic compound, preparation method, intermediate, pharmaceutical composition and use. WO2018086593. 2018.
  • Medshine Discovery Inc. Toll-like receptor-7 agonist. WO2016107536. 2016.
  • Medshine Discovery Inc. Isothiazolo[4,3-d]pyrimidine-5,7-diamine derivative as TLR8 agonist. WO2018233648. 2018.
  • Novartis AG Compounds and compositions as toll-like receptor 7 agonists. WO2015168269. 2015.
  • Novartis AG Antibody conjugates comprising toll-like receptor agonist. WO2017072662. 2017.
  • Novartis AG Antibody conjugates comprising toll-like receptor agonist and combination therapies. WO2018198091. 2018.
  • Primmune Therapeutics, Inc. TLR7 agonists. WO2019226977. 2019.
  • Shenzhen Hornetcorn Biotechnology Company,Co., Ltd. Purine-scaffold TLR7 ligands and conjugate thereof. WO2017197624. 2017.
  • Silverback Therapeutics, Inc. Benzazepine compounds, conjugates, and uses thereof. WO2018170179. 2018.
  • Silverback Therapeutics, Inc. Substituted benzazepine compounds, conjugates, and uses thereof. WO2020056198. 2020.
  • Silverback Therapeutics, Inc. Tumor targeting conjugates and methods of use thereof. WO2018140831. 2018.
  • Silverback Therapeutics, Inc. Antibody conjugates of toll-like receptor agonists. WO2020056192. 2020.
  • Silverback Therapeutics, Inc. Compositions for the treatment of disease with immune stimulatory conjugates. WO2020056008. 2020.
  • Torque Therapeutics, Inc. TLR7/8 agonists and liposome compositions. WO2020023680. 2020.
  • Tsinghua University. Pyridopyrimidine derivatives or salts thereof, preparation method therefor, and pharmaceutical composition and uses thereof. WO2019095455. 2019.
  • University of Kansas. Toll-like receptor 8 agonists. WO2015095780. 2015.
  • Beesu M, Malladi SS, Fox LM, et al. Human Toll-like receptor 8-selective agonistic activities in 1-alkyl-1H-benzimidazol-2-amines. J Med Chem. 2014 Sep 11;57(17):7325–7341.
  • University of Kansas. Human TLR8-selective agonists. WO2017034986. 2017.
  • University of Kansas. Toll-like receptor agonists. WO2015023958. 2015.
  • Regents of the University of Minnesota. Pyrimidines and uses thereof. US20180215720. 2018.
  • Regents Of The University of Minnesota. Therapeutic compounds and methods of use thereof. WO2020009946. 2020.
  • Tanji H, Ohto U, Shibata T, et al. Structural reorganization of the toll-like receptor 8 dimer induced by agonistic ligands. Science. 2013;339(6126):1426–1429.
  • Tanji H, Ohto U, Shibata T, et al. Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat Struct Mol Biol. 2015 Feb 01;22(2):109–115.
  • Zo U Z, Shibata T, Krayukhina E, et al. Structural analysis reveals that toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA. Immunity. 2016;45(4):737–748.
  • Zhang Z, Ohto U, Shibata T, et al. Structural analyses of toll-like receptor 7 reveal detailed RNA sequence specificity and recognition mechanism of agonistic ligands. Cell Rep. 2018;25(12):3371–3381.
  • Patel MC, Shirey KA, Pletneva LM, et al. Novel drugs targeting Toll-like receptors for antiviral therapy. Future Virol. 2014;9(9):811–829.
  • Tisoncik JR, Korth MJ, Simmons CP, et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012 Mar;76(1):16–32.
  • Gane E, Folitar I, Schwabe C, et al. RO7020531, a novel prodrug of a toll-like receptor 7 agonist, is safe, well tolerated and activates TLR signaling in healthy volunteers. J Hepatol. 2018;68:S514–S515.
  • Janssen HLA, Brunetto MR, Kim YJ, et al. Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. J Hepatol. 2018 Mar;68(3):431–440.
  • Gilead Announces New Data from Viral Hepatitis Research Programs at the Liver Meeting 2019 - Data on Investigational TLR8 Agonist GS-9688 Support Continued Advancement of the Company's HBV Cure Research Program [Press release 8 Nov 2019].
  • Polakis P. Antibody Drug Conjugates for Cancer Therapy. Pharmacol Rev. 2016 Jan;68(1):3–19.
  • Landenberger L. Silverback edges toward IND and clinic with a $78.5M series B. BioWorld (online addition). 11 March 2020.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.