Structure-Based Optimization of Angiostatic Agent 6DBF7, an Allosteric Antagonist of Galectin-1

Dings, Ruud P.M.; Kumar, Nigam; Miller, Michelle C.; Loren, Melissa L.; Rangwala, Huzaifa; Hoye, Thomas R.; Mayo, Kevin H.

doi:10.1124/jpet.112.199646

Cited by 40 publications

(31 citation statements)

References 57 publications

(74 reference statements)

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“…Interestingly, the Gal-1 inhibitor OTX008, which is not a classical carbohydrate binding region competitor, was recently shown to synergize with rapamycin to block tumor growth [ 36 ]. Intriguingly, an OTX008 related compound binds at a Gal-1 site that may allosterically affect its binding to Raf-effectors or Gal-1 dimerization and hence its nanocluster scaffolding activity [ 37 ]. More generally, our work suggests that rapalog treatment should be combined specifically with H-ras signaling inhibition to prevent possibly detrimental shifts in MAPK- and Akt-signaling with consequences for stemness induction.…”

Section: Discussionmentioning

confidence: 99%

Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner

et al. 2017

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Currently several combination treatments of mTor- and Ras-pathway inhibitors are being tested in cancer therapy. While multiple feedback loops render these central signaling pathways robust, they complicate drug targeting.Here, we describe a novel H-ras specific feedback, which leads to an inadvertent rapalog induced activation of tumorigenicity in Ras transformed cells. We find that rapalogs specifically increase nanoscale clustering (nanoclustering) of oncogenic H-ras but not K-ras on the plasma membrane. This increases H-ras signaling output, promotes mammosphere numbers in a H-ras-dependent manner and tumor growth in ovo. Surprisingly, also other FKBP12 binders, but not mTor-inhibitors, robustly decrease FKBP12 levels after prolonged (>2 days) exposure. This leads to an upregulation of the nanocluster scaffold galectin-1 (Gal-1), which is responsible for the rapamycin-induced increase in H-ras nanoclustering and signaling output. We provide evidence that Gal-1 promotes stemness features in tumorigenic cells. Therefore, it may be necessary to block inadvertent induction of stemness traits in H-ras transformed cells by specific Gal-1 inhibitors that abrogate its effect on H-ras nanocluster. On a more general level, our findings may add an important mechanistic explanation to the pleiotropic physiological effects that are observed with rapalogs.

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Section: Discussionmentioning

confidence: 99%

Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner

et al. 2017

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“…The cell types involved in the secretion and release of Gal 1 include human/porcine keratinocytes, thymic epithelial cells, fibroblasts, 3T3 cells, T-and B-cells, macrophages, dendritic cells, Langerhans cells, cultured stromal cells of human bone marrow, endothelial cells, and ovary cells (11)(12)(13). Various Gal 1 ligands are found on lymphocytes (CD7, CD43, and CD45), on endothelial cells (CD13, CD36, ROBO4, and integrins), and in the extracellular matrix (fibronectin, integrins, laminin, ROBO4, and GM1) (14).…”

Section: Introductionmentioning

confidence: 99%

Galectin 1 in dermatology: current knowledge and perspectives

Pasmatzi

Papadionysiou

Monastirli

et al. 2019

Acta Dermatovenerologica Alpina Pannonica Et Adriatica

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Gal 1, the first identified and best-studied prototypical member of the galectin family, is encoded in humans by the LGALS1 gene, which is located on chromosome 22 (q12) (10). It is a noncovalent homodimeric protein with a 14 kDa monomer that contains one CRD and preferentially recognizes galactose-β1-4-N-acetyl-glucosamine sequences on N-or O-linked glycans (11). AbstractGalectins are a family of soluble proteins that are widely distributed in nature and bind to a variety of glycoproteins and glycolipids bearing β-galactoside residues. They are involved in highly important processes at the molecular and cellular level in human cutaneous and extracutaneous tissues, and they exert biological effects of paramount importance through their interaction with cytoplasmic and nuclear proteins and the components of the cell surface and extracellular matrix. Galectin 1 (Gal 1), the first galectin isolated, is a noncovalent homodimeric protein with a 14 kDa monomer that contains one carbohydrate-recognition domain (CRD) and preferentially recognizes galactose-β1-4-N-acetyl-glucosamine sequences on N-or O-linked glycans. Gal 1 occurs intracellularly, extracellularly, and on the cell surface. In the last few years Gal 1 has emerged as a multifaceted protein that exerts a wide spectrum of regulatory effects in diverse normal and abnormal tissues and conditions, indicating a tremendous therapeutic potential. This review summarizes current knowledge on the expression of Gal 1 in normal and diseased human skin, its implications in the pathogenesis, diagnosis, and prognosis of cutaneous disorders, and the novel approach to the treatment of these disorders offered by the use of Gal 1 or its inhibitors/antagonists.

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“…The first point concerning enhancement of galectin-1 affinity was refuted by others using in vitro NMR studies showing decreased cell-surface binding by anginex attenuated galectin-1, [116,117] however the second aspect concerning non-selectivity of anginex was not further studied.…”

Section: Peptide-based Inhibitorsmentioning

confidence: 99%

“…[123] Further efforts to increase solubility and efficacy resulted in two compounds with the desired effects: DB16 (SVQMKL-[DBF]-AIVKLNA) and DB21 (SVQNvaKL-[DBF]-IIVKLNA). [117] The partial peptidomimetics are reportedly more potent in vivo than its ancestor, anginex, despite showing weaker effects in vitro, which the authors postulate is due to increased bioavailability. [123] Further developing from the partial peptidomimetics, a series of topomimetics were designed utilising the calix [4]arene scaffold (Fig.…”

Section: Peptide-based Inhibitorsmentioning

confidence: 99%

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

2014

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Galectins are a family of galactoside-specific lectins that are involved in a myriad of metabolic and disease processes. Due to roles in cancer and inflammatory and heart diseases, galectins are attractive targets for drug development. Over the last two decades, various strategies have been used to inhibit galectins, including polysaccharide-based therapeutics, multivalent display of saccharides, peptides, peptidomimetics, and saccharide-modifications. Primarily due to galectin carbohydrate binding sites having high sequence identities, the design and development of selective inhibitors targeting particular galectins, thereby addressing specific disease states, is challenging. Furthermore, the use of different inhibition assays by research groups has hindered systematic assessment of the relative selectivity and affinity of inhibitors. This review summarises the status of current inhibitors, strategies, and novel scaffolds that exploit subtle differences in galectin structures that, in conjunction with increasing available data on multiple galectins, is enabling the feasible design of effective and specific inhibitors of galectins. small-molecule crystallography, University of London, UK) undertook post-doctoral research in protein X-ray crystallography and drug-design in academia and industry within Canada, USA, Switzerland and Australia. In 2002 Helen established a protein X-ray crystallography structural biology group at the Institute for Glycomics, Griffith University. As recognition of her international contribution to structural biology and chemistry she was admitted as fellow of the Royal Society of Chemistry (FRSC) in 2006. Her research involves determination of atomic protein structure, analysis of protein-ligand interactions and application of this information in understanding protein function and for structure based drug-design. Her research group has a major focus on lectins critical to disease progression including her research program on galectins that have importance in serious conditions including cancer. Khuchtumur Bum-Erdene completed his Bachelors degree in Chemistry (

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Structure-Based Optimization of Angiostatic Agent 6DBF7, an Allosteric Antagonist of Galectin-1

Cited by 40 publications

References 57 publications

Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner

Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner

Galectin 1 in dermatology: current knowledge and perspectives

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

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