An updated patent review of galectin-1 and galectin-3 inhibitors and their potential therapeutic applications (2016–present)

References

• Barondes SH, Cooper DN, Gitt MA, et al. Structure and function of a large family of animal lectins. J Biol Chem. 1994 Aug 19;269(33):20807–20810.
   PubMed Web of Science ®Google Scholar
• Johannes L, Jacob R, Leffler H. Galectins at a glance. J Cell Sci. 2018 May 1;131(9):1–9.
   Web of Science ®Google Scholar
• Leffler H, Carlsson S, Hedlund M, et al. Introduction to galectins. Glycoconj J. 2002 Jan 1;19(7–9):433–440.
   PubMed Web of Science ®Google Scholar
• Yang RY, Rabinovich GA, Liu FT. Galectins: structure, function and therapeutic potential. Expert Rev Mol Med. 2008 Jun;10:1–24.
   Google Scholar
• Mayo KH. From carbohydrate to peptidomimetic inhibitors of galectins. In: Galectins and disease implications for targeted therapeutics. American Chemical Society. 2012. p. 61–77. DOI: 10.1021/bk-2012-1115.ch003.
   Google Scholar
• Ingrassia L, Camby I, Lefranc F, et al. Anti-galectin compounds as potential anti-cancer drugs. Curr Med Chem. 2006 Dec 1;13(29):3513–3527.
   PubMed Web of Science ®Google Scholar
• Blanchard H, Yu X, Collins PM, et al. Galectin-3 inhibitors: a patent review (2008–present). Expert Opin Ther Pat. 2014Oct1;24(10):1053–1065.
   PubMed Web of Science ®Google Scholar
• Blanchard H, Bum-Erdene K, Bohari MH, et al. Galectin-1 inhibitors and their potential therapeutic applications: a patent review. Expert Opin Ther Pat. 2016May3;21(5):100411–100454.
   Google Scholar
• Öberg CT, Leffler H, Nilsson UJ. Inhibition of galectins with small molecules. Chimia (Aarau). 2011 Feb 23;30(172):18–23.
   Google Scholar
• Pieters RJ. Inhibition and detection of galectins. ChemBioChem. 2006 May 5;7(5):721–728.
   PubMed Web of Science ®Google Scholar
• Denavit V, Lainé D, Tremblay T, et al. Inhibitors of galectins: structures and Syntheses. trends glycosci. Glycotechnol. 2018 Jan 25;30(172):SE21–40.
   Web of Science ®Google Scholar
• Bertuzzi S, Quintana JI, Ardá A, et al. Targeting galectins with glycomimetics. Front Chem. 2020 Aug 7;8:593. .
   PubMed Web of Science ®Google Scholar
• Hirabayashi J, Hashidate T, Arata Y, et al. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. BBA-General Subjects. 2002 Sep 19;1572(2–3):232–254.
   PubMed Web of Science ®Google Scholar
• Vasta GR. Roles of galectins in infection. Nat Rev Microbiol. 2009 Jun;7(6):424–438.
   PubMed Web of Science ®Google Scholar
• Thiemann S, Baum LG. Galectins and immune responses—just how do they do those things they do? Annu. Rev Immunol. 2016 May 20;34(1):243–264.
   Google Scholar
• Modenutti CP, Capurro JI, Di Lella S, et al. The structural biology of galectin-ligand recognition: current advances in modeling tools, protein engineering, and inhibitor design. Front Chem. 2019 Dec;7(7):823.
   PubMedGoogle Scholar
• Liu FT, Patterson RJ, Wang JL. Intracellular functions of galectins. Biochim. Biophys Acta. 2002 Sep 19;1572(2–3):263–273.
   PubMed Web of Science ®Google Scholar
• Camby I, Le Mercier M, Lefranc F, et al. Galectin-1: a small protein with major functions. Glycobiology. 2006 Nov 1;16(11):137R–57R.
   PubMed Web of Science ®Google Scholar
• Kadoya T, Horie H. Structural and functional studies of galectin-1: a novel axonal regeneration-promoting activity for oxidized galectin-1. Curr Drug Targets. 2005 Jun 1;6(4):375–383.
   PubMed Web of Science ®Google Scholar
• Patterson RJ, Wang W, Wang JL. Understanding the biochemical activities of galectin-1 and galectin-3 in the nucleus. Glycoconj J. 2002 Jan 1;19(7–9):499–506.
   PubMed Web of Science ®Google Scholar
• He J, Baum LG. Galectin interactions with extracellular matrix and effects on cellular function. Methods Enzymol. 2006 Jan ;1(417):247–256.
   Google Scholar
• Gauthier L, Rossi B, Roux F, et al. Galectin-1 is a stromal cell ligand of the pre-B cell receptor (BCR) implicated in synapse formation between pre-B and stromal cells and in pre-BCR triggering. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13014–13019.
   PubMed Web of Science ®Google Scholar
• Ilarregui JM, Croci DO, Bianco GA, et al. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat Immunol. 2009 Sep;10(9):981–991.
   PubMed Web of Science ®Google Scholar
• Dias-Baruffi M, Zhu H, Cho M, et al. Dimeric galectin-1 induces surface exposure of phosphatidylserine and phagocytic recognition of leukocytes without inducing apoptosis. J Biol Chem. 2003 Oct 17;278(42):41282–41293.
   PubMed Web of Science ®Google Scholar
• Rubinstein N, Alvarez M, Zwirner NW, et al. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection: a potential mechanism of tumor-immune privilege. Cancer Cell. 2004 Mar 1;5(3):241–251.
   PubMed Web of Science ®Google Scholar
• Perillo NL, Marcus ME, Baum LG. Galectins: versatile modulators of cell adhesion, cell proliferation, and cell death. J Mol Med. 1998 Apr 1;76(6):402–412.
   PubMed Web of Science ®Google Scholar
• D’Haene N, Sauvage S, Maris C, et al. VEGFR1 and VEGFR2 involvement in extracellular galectin-1-and galectin-3-induced angiogenesis. PloS One. 2013 Jun 17;8(6):e67029.
   PubMed Web of Science ®Google Scholar
• Goldring K, Jones GE, Thiagarajah R, et al. The effect of galectin-1 on the differentiation of fibroblasts and myoblasts in vitro. J Cell Sci. 2002 Jan 15;115(Pt 2):355–366.
   PubMed Web of Science ®Google Scholar
• Gaudet AD, Steeves JD, Tetzlaff W, et al. Expression and functions of galectin-1 in sensory and motoneurons. Curr Drug Targets. 2005 Jun 1;6(4):419–425.
   PubMed Web of Science ®Google Scholar
• Wada M, Ono S, Kadoya T, et al. Decreased galectin-1 immunoreactivity of the skin in amyotrophic lateral sclerosis. J Neurol Sci. 2003 Apr 15;208(1–2):67–70.
   PubMed Web of Science ®Google Scholar
• St-Pierre C, Ouellet M, Tremblay MJ, et al. Galectin-1 and HIV-1 infection. Meth Enzymol. 2010 Jan 1;480::267–294.
   PubMed Web of Science ®Google Scholar
• Rabinovich GA. Galectin-1 as a potential cancer target. Br J Cancer. 2005 Apr;92(7):1188–1192.
   PubMed Web of Science ®Google Scholar
• Mercier S, St-Pierre C, Pelletier I, et al. Galectin-1 promotes HIV-1 infectivity in macrophages through stabilization of viral adsorption. Virology. 2008 Feb 5;371(1):121–129.
   PubMed Web of Science ®Google Scholar
• Thijssen VL, Heusschen R, Caers J, et al. Galectin expression in cancer diagnosis and prognosis: a systematic review. Biochim Biophys Acta. 2015 Apr 1;1855(2):235–247.
   PubMed Web of Science ®Google Scholar
• Dumic J, Dabelic S, Flögel M. Galectin-3: an open-ended story. Biochim Biophys Acta Gen Subj. 2006 Apr 1;1760(4):616–635.
   PubMed Web of Science ®Google Scholar
• Newlaczyl AU, Yu LG. Galectin-3–a jack-of-all-trades in cancer. Cancer Lett. 2011 Dec 27;313(2):123–128.
   PubMed Web of Science ®Google Scholar
• Iacobini C, Amadio L, Oddi G, et al. Role of galectin-3 in diabetic nephropathy. J Am Soc Nephrol. 2003 Aug 1;14(suppl 90003):S264–70.
   PubMedGoogle Scholar
• Funasaka T, Raz A, Nangia-Makker P. Galectin-3 in angiogenesis and metastasis. Glycobiology. 2014 Oct 1;24(10):886–891.
   PubMed Web of Science ®Google Scholar
• Liu FT. Regulatory roles of galectins in the immune response. Int Arch Allergy Immunol. 2005;136(4):385–400.
   PubMed Web of Science ®Google Scholar
• Rabinovich GA, Liu FT, Hirashima M, et al. An emerging role for galectins in tuning the immune response: lessons from experimental models of inflammatory disease, autoimmunity and cancer. Scand J Immunol. 2007 Aug;66(2–3):143–158.
   PubMed Web of Science ®Google Scholar
• Cao Z, Said N, Amin S, et al. Galectins-3 and-7, but not galectin-1, play a role in re-epithelialization of wounds. J Biol Chem. 2002 Nov 1;277(44):42299–42305.
   PubMed Web of Science ®Google Scholar
• Suthahar N, Meijers WC, Silljé HH, et al. Galectin-3 activation and inhibition in heart failure and cardiovascular disease: an update. Theranostics. 2018;8(3):593.
   PubMed Web of Science ®Google Scholar
• Ramírez Hernández E, Sánchez-Maldonado C, Mayoral Chávez MA, et al. The therapeutic potential of galectin-1 and galectin-3 in the treatment of neurodegenerative diseases. Expert Rev Neurother. 2020 May 3;20(5):439–448.
   PubMed Web of Science ®Google Scholar
• Gao Z, Liu Z, Wang R, et al. Galectin-3 is a potential mediator for atherosclerosis. J Immunol Res. 2020 Feb;2020:5284728. DOI:10.1155/2020/5284728.
   Web of Science ®Google Scholar
• Gao P, Simpson JL, Zhang J, et al. Galectin-3: its role in asthma and potential as an anti-inflammatory target. Respir Res. 2013 Dec 1;14(1):136.
   PubMedGoogle Scholar
• Sethi A, Sanam S, Munagalasetty S, et al. Understanding the role of galectin inhibitors as potential candidates for SARS-CoV-2 spike protein:in silicostudies. RSC Adv. 2020 Aug 13;8(3):29873–29884.
   Google Scholar
• Blanchard H, Bum-Erdene K, Hugo MW. Inhibitors of galectins and implications for structure-based design of galectin-specific therapeutics. Aust J Chem. 2014 Dec 24;67(12):1763–1779.
   Web of Science ®Google Scholar
• Fang T, Liu DD, Ning HM, et al. Modified citrus pectin inhibited bladder tumor growth through downregulation of galectin-3. Acta Pharmacol Sin. 2018 Dec;39(12):1885–1893.
   PubMed Web of Science ®Google Scholar
• Miller MC, Klyosov A, Mayo KH. The α-galactomannan Davanat binds galectin-1 at a site different from the conventional galectin carbohydrate binding domain. Glycobiology. 2009 Sep 1;19(9):1034–1045.
   PubMed Web of Science ®Google Scholar
• Salomonsson E, Thijssen VL, Griffioen AW, et al. The anti-angiogenic peptide anginex greatly enhances galectin-1 binding affinity for glycoproteins. J Biol Chem. 2011 Apr 22;286(16):13801–13804.
   PubMed Web of Science ®Google Scholar
• Dings RP, Kumar N, Miller MC, et al. Structure-based optimization of angiostatic agent 6DBF7, an allosteric antagonist of galectin-1. J Pharmacol Exp Ther. 2013 Mar 1;344(3):589–599.
   PubMed Web of Science ®Google Scholar
• Astorgues-Xerri L, Riveiro ME, Tijeras-Raballand A, et al. OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis. Eur J Cancer. 2014 Sep 1;50(14):2463–2477.
   PubMed Web of Science ®Google Scholar
• Dings RP, Miller MC, Nesmelova I, et al. Antitumor agent calixarene 0118 targets human galectin-1 as an allosteric inhibitor of carbohydrate binding. J Med Chem. 2012Jun14;55(11):5121–5129.
   PubMed Web of Science ®Google Scholar
• Shih TC, Liu R, Fung G, et al. A novel galectin-1 inhibitor discovered through one-bead two-compound library potentiates the antitumor effects of paclitaxel in vivo. Mol Cancer Ther. 2017 Jul 1;16(7):1212–1223.
   PubMed Web of Science ®Google Scholar
• Goud NS, Ghouse MS, Vishnu J, et al. Synthesis and biological evaluation of novel heterocyclic imines linked coumarin-thiazole hybrids as anticancer agents. anticancer. Agents Med Chem. 2019 Mar 1;19(4):557–566.
   PubMed Web of Science ®Google Scholar
• Goud NS, Ghouse SM, Vishnu J, et al. Synthesis of 1-benzyl-1H-benzimidazoles as galectin-1 mediated anticancer agents. Bioorg Chem. 2019 Aug ;89(89):103016.
   PubMedGoogle Scholar
• Wang C, Wang Y, Ma SR, et al. Berberine inhibits adipocyte differentiation, proliferation and adiposity through down-regulating galectin-3. Sci Rep. 2019 Sep 16;9(1):1–8.
   PubMed Web of Science ®Google Scholar
• Goud NS, Makani VK, Pranay J, et al. Synthesis18 F-radiolabeling and apoptosis inducing studies of novel 4, 7-disubstituted coumarins. Bioorg Chem. 2020 Apr 1;97:103663. .
   PubMed Web of Science ®Google Scholar
• Gabr M, Rehman AU, Chen HF. Quinoline-pyrazole scaffold as a novel ligand of galectin-3 and suppressor of TREM2 signaling. ACS Med Chem Lett. 2020 Aug 11;11(9):1759–1765.
   PubMed Web of Science ®Google Scholar
• Goud NS, Pooladanda V, Chandra KM, et al. Novel benzimidazole-triazole hybrids as apoptosis inducing agents in lung cancer: design, synthesis, 18F-radiolabeling & galectin-1 inhibition studies. Bioorg Chem. 2020 Sep 1;102:104125. .
   PubMed Web of Science ®Google Scholar
• Sethi A, Sasikala K, Jakkula P, et al. Synthesis and computational studies involving indole-coumarin hybrids as galectin-1 inhibitors. Chem Pap. 2021. 10.1007/s11696-021-01534-w
   PubMedGoogle Scholar
• Kahsai AW, Cui J, Hü K, et al. Analogs of tetrahydroisoquinoline natural products that inhibit cell migration and target galectin-3 outside of its carbohydrate-binding site. J Biol Chem. 2008 Sep 5;19(4):557–566.
   Google Scholar
• Sirois S, Giguère D, Roy R. A first QSAR model for galectin-3 glycomimetic inhibitors based on 3D docked structures. Med Chem. 2006 Sep 1;2(5):481–489.
   PubMedGoogle Scholar
• Sethi A, Sanam S, Alvala M. New clues arising from hunt of saccharides binding to galectin 3 via 3D QSAR and docking studies. Inform Med Unlocked. 2020 Jan 1;21:100411. .
   Google Scholar
• Girard A, Magnani JL. Clinical trials and applications of galectin antagonists Trends Glycosci. Glycotechnol. 2018 May 25;30(172):SE211–20.
   Google Scholar
• ClinicalTrials.gov, A first in human study to evaluate the safety, tolerability and pharmacokinetics of GB1211 in healthy subjects and in subjects with suspected non-alcoholic steato-hepatitis (NASH) and liver fibrosis. [cited 2020 10 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT03809052
   Google Scholar
• ClinicalTrials.gov, Study Evaluating the Efficacy and Safety of Belapectin (GR-MD-02) for the Prevention of Esophageal Varices in NASH Cirrhosis. [cited 2020 10 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT04365868
   Google Scholar
• ClinicalTrials.gov, A Study to Test the Efficacy and Safety of Inhaled TD139 in Subjects With Idiopathic Pulmonary Fibrosis (IPF).[cited 2020 10 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT03832946
   Google Scholar
• ClinicalTrials.gov, Rapid Experimental Medicine for COVID-19 (DEFINE). https://clinicaltrials.gov/ct2/show/NCT04473053
   Google Scholar
• Galecto’s Oral A Galectin-3 Inhibitor GB1211 Well Tolerated in Phase I Clinical Data Presented Recently at Several Scientific Conferences. 2020 Sept 15. [cited 2020 10 10]. Available from: https://galecto.com/gb1211-data/
   Google Scholar
• ClinicalTrials.gov, Study of Efficacy and Safety of MBG453 in Combination With Azacitidine in Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2) (STIMULUS-MDS2). [cited 2020 10 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT04266301
   Google Scholar
• ClinicalTrials.gov, A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy (STIMULUS-AML1). [cited 2020 10 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT04150029
   Google Scholar
• Nilsson U, Leffler H, Henderson N, et al. Galactoside inhibitor of galectin-3 and its use for treating pulmonary fibrosis. CA2794066C2017/0228. 2017.
   Google Scholar
• Nilsson U LH, Zetterberg F Novel galactoside inhibitors of galectins. WO2016/005311A1. 2016.
   Google Scholar
• Brimert T, Johnsson R, Leffler H, et al. Novel hybrid galactoside inhibitor of galectins. WO 2016/113335 A1. 2016.
   Google Scholar
• Brimert T, Johnsson R, Leffler H, et al. 1,1 ‘-sulfanediyl-di-beta-d-galactopyranosides as inhibitors of galectins. WO2017080973A1. 2017.
   Google Scholar
• George R, Johnson JM, Nir R, et al. Selenogalactoside compounds for the prevention and treatment of diseases associated with galectin and the use thereof. WO2017152048A1. 2017.
   Google Scholar
• Lam KS, Liu R, Tsung-Chieh SHLLS Compounds for treatment of cancer. WO2017176767A1. 2017.
   Google Scholar
• Beno BR, Ellsworth BA, Feng J, et al. Small molecule inhibitors of galectin-3. WO2019067702A1. 2019.
   Google Scholar
• Ellsworth BA, Feng J, Liu C, et al. Small molecule inhibitors of galectin-3. WO2020198266A1. 2020.
   Google Scholar
• Clofent-Sanchez G, Cérutti M, Fontayne A, et al. A specific binding molecule directed against galectin-3 protein. WO2019068863A1. 2019.
   Google Scholar
• Hartz RA, Jalagam PR, Nair SK, et al. Tetrahydropyran-based thiodisaccharide mimics as galectin-3 inhibitors. WO2019241461A1. 2019
   Google Scholar
• Saarinen J, Satomaa T Conjugates. WO2020002765A1. 2020.
   Google Scholar
• Nilsson U, Zetterberg F Prodrug of galactoside inhibitors of galectins. WO2020078807A1. 2020.
   Google Scholar
• Jansson K, Peterson K, Zetterberg F Alpha-D-galactoside inhibitors of galectins. WO2020104335A1. 2020.
   Google Scholar
• Ghosh I, Magnani JL, Noguiera J, et al. Galectin-3 inhibiting C-glycosides. WO2020139960A1. 2020.
   Google Scholar
• Ghosh I, Magnani JL, Noguiera J, et al. Heterobifunctional inhibitors of e-selectin and galectin-3. (WO2020139962A1):2020.
   Google Scholar
• Nilsson U, Leffler H, Mukhopadhyay B, et al. Galectoside inhibitors of galectins. US. 2016;9353141.
   Google Scholar
• Sabbah HN Method for treating diastolic heart failure by inhibiting galectin-3. US20190000872A1. 2019.
   Google Scholar
• Gao X, Zhi Y, Zhang T, et al. Analysis of the neutral polysaccharide fraction of MCP and its inhibitory activity on galectin-3. Glycoconj J. 2012 May;;29(4):159–165.
   PubMed Web of Science ®Google Scholar
• Giguere D, ST-Gelais J, Denavit V Synthesis of 3-Azido-3-Deoxy-D-galactopyranose. WO2020248068A1.2020.
   Google Scholar
• St-Gelais J, Denavit V, Giguère D. Efficient synthesis of a galectin inhibitor clinical candidate (TD139) using a Payne rearrangement/azidation reaction cascade. Org Biomol Chem. 2020 May 7;18(20):3903–3907.
   PubMed Web of Science ®Google Scholar
• Stegmayr J, Zetterberg F, Carlsson MC, et al. Extracellular and intracellular small-molecule galectin-3 inhibitors. Sci Rep. 2019Feb18;9(1):1–2.
   PubMedGoogle Scholar
• Bratteby K, Torkelsson E, L’Estrade ET, et al. In vivo veritas: 18F-radiolabeled glycomimetics allow insights into the pharmacological fate of galectin-3 inhibitors. J Med Chem. 2019Dec17;63(2):747–755.
   Web of Science ®Google Scholar