Design, synthesis, and biological evaluation of bifunctional thyrointegrin inhibitors: new anti-angiogenesis analogs

Bridoux, Alexandre; Khan, Riaz A.; Chen, Celei; Chevé, Gwénaël; Cui, Huadong; Dyskin, Evgeny; Yasri, Abdelaziz; Mousa, Shaker A.

doi:10.3109/14756366.2011.557023

Cited by 13 publications

(5 citation statements)

References 71 publications

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“…Our molecular simulation studies showed that, similar to RGD, the carboxylic acid group of tetrac will bind to Mn 2+ and the Asn 215 amino acid of the β3 subunit of α v β 3 , but it is unlikely that tetrac can reach the α v -subunit (Figure S1A), unlike the guanidine group of RGD that can bind to Asp 150 and Asp 218 amino acids of the α v subunit (Figure S1B). 52 An outline of the synthetic route for the alkyne-modified tetrac 1 is shown in Scheme 2. We first protected the phenyl acetic acid end of tetrac 1 to methyl ester using a previously published protecting method 29 by dissolving 1 in CH 3 OH and SOCl 2 .…”

Section: ■ Introductionmentioning

confidence: 99%

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin α_vβ₃ Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme

et al. 2019

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Discovery of bioactive molecules that target integrins has implicated their role in tumor angiogenesis, tumor growth, metastasis, and other pathological angiogenesis processes. Integrins are members of a family of cell surface receptors that play a critical role in the angiogenesis process. Tetraiodothyroacetic acid (tetrac), a deaminated derivative of l-thyroxine (T4), is a “thyrointegrin” antagonist that blocks the actions of l-triiodothyronine (T3) and T4 with an interaction site that is located at or near the RGD recognition site identified on integrin αvβ3’s binding pocket (thyrointegrin αvβ3 receptors). We have enhanced the biological activity of a tetrac-based inhibitor via significantly improving its αvβ3 receptor binding affinity by introducing a triazole ring on the outer ring of tetrac and covalently conjugating to polymer to increase the product’s hydrophilicity via PEGylation. The product, P-bi-TAT, was restricted from nuclear translocation and demonstrated high blood brain barrier permeability and retention in contrast to the non-PEG conjugated derivative. Results of biological activity indicated that this macromolecule new chemical entity P-bi-TAT has greater than 400-fold potent integrin αvβ3 affinity versus the parent compound tetrac and has potent anticancer/anti-angiogenesis efficacy against glioblastoma multiforme (GBM). P-bi-TAT administered subcutaneously once daily for 21 days at 1–10 mg/kg mouse body weight resulted in a dose-dependent suppression of GBM tumor growth and viability as monitored with IVIS imaging (P < 0.001). GBM tumors had >95% volume loss and maximal loss of GBM cell viability during the 21 days ON-treatment experiment as well as in the 21 days ON followed by 21 days OFF-treatment experiment (P < 0.001). In conclusion, P-bi-TAT is a promising lead clinical candidate effective in the treatment of human GBM.

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Section: ■ Introductionmentioning

confidence: 99%

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin α_vβ₃ Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme

et al. 2019

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“…Another way of controlling neuroblastoma tumor growth has been to inhibit or control angiogenesis, which is the formation of new blood vessels from pre-existing ones that feed growing tumors with oxygen and nutrients. Previous investigations from our laboratory and by others demonstrated that various neuroblastoma cells and angiogenic endothelial cells highly express the integrin αvβ3 receptor. − Integrin receptors are heterodimeric glycoproteins consisting of different α and β subunits . Many integrin receptors, including the αvβ3 receptor, are involved in angiogenesis.…”

Section: Introductionmentioning

confidence: 96%

“…19−22 Integrin receptors are heterodimeric glycoproteins consisting of different α and β subunits. 23 most other integrin receptors bind ligands such as tripeptide Arg-Gly-Asp (RGD)-containing adhesive proteins, vitronectin, osteopontin, and fibrinogen. Therefore, the selectivity of antagonists for the integrin αvβ3 receptor plays a crucial role in targeted antiangiogenic cancer therapy.…”

Section: ■ Introductionmentioning

confidence: 99%

Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvβ3 Receptors in the Treatment of Neuroblastoma

et al. 2020

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Therapeutic targeting of the norepinephrine transporter (NET) function with benzylguanidine (BG), conjugated with the high-affinity thyrointegrin αvβ3 antagonist triazole tetraiodothyroacetic acid, TAT, via noncleavable bonding to poly(ethylene glycol) (PEG 400 ) (P) might allow for effective treatment options in neuroblastoma. BG-P-TAT is a dual-targeting agent, targeting the NET function and the thyrointegrin αvβ3 receptors that are overexpressed in neuroblastoma and other neuroendocrine tumors. Various cancer cells and actively dividing tumor-endothelial cells express the thyrointegrin αvβ3 receptors. In this work, the novel compound BG-P-TAT was synthesized and evaluated in the neuroblastoma SK-N-FI cell line for improved targeting and to offer a new strategy for patients with neuroblastoma. BG-P-TAT demonstrated significant suppression of neuroblastoma tumor progression, growth, and viability in a dose-dependent manner. In conclusion, BG-P-TAT represents a potential lead candidate for the treatment of neuroblastoma and other neuroendocrine tumors.

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“…They are critical to leukocytes’ function and to the angiogenesis process, particularly local release of growth factors that are generously overexpressed and produced by cancer cells and by dividing endothelial cells of tumor-relevant blood vessels. There are different members of the integrin family including αvβ3, αvβ5, and α5β1 that are involved in angiogenesis and have high affinity to arginine–glycine–aspartate (RGD) extracellular matrix (ECM)-containing angiogenesis modulators such as fibronectin, fibrinogen, and ostepontin ( 8 – 10 ). αvβ3 (thyrointegrin) is generously expressed by cancer cells and by dividing endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Targeting Thyrointegrin αvβ3 Using Fluorobenzyl Polyethylene Glycol Conjugated Tetraiodothyroacetic Acid (NP751) in Acute Myeloid Leukemia

et al. 2022

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BackgroundAcute myeloid leukemia (AML) is associated with poor long-term survival, even with newer therapeutic agents. Here, we show the results of our preclinical study, in which we evaluated the efficacy of a new thyrointegrin αvβ3 antagonist, named fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (fb-PMT).Methods and Resultsfb-PMT (NP751) is a potent αvβ3 antagonist of molecular weight of 2,478.9 Da. it represents a conjugate of tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol (PEG36), with a 4-fluorobenzyl group capping the other end of the PEG. fb-PMT effectively suppresses the malignant growth of human acute myeloid leukemia (AML) after successful engraftment in transgenic NSG-S xenograft mouse models of either established human AML cell line or primary AML cells. Daily treatment with fb-PMT (1–10 mg/kg body weight) subcutaneously (s.c.) for 3–4 weeks was associated with marked regression of leukemogenesis and extended survival in both models. The efficiency of the fb-PMT therapy was verified using in vivo imaging system (IVIS) imaging, flow cytometry, and histopathological examination to monitor the engraftment of leukemic cells in the bone marrow and other organs. fb-PMT therapy for 3–4 weeks at 3 and 10 mg/kg daily doses exhibited significant reduction (p < 0.0001) of leukemic cell burden of 74% and >95%, respectively. All fb-PMT-treated mice in the 10 mg/kg treatment arm successfully maintained remission after discontinuing the daily treatment. Comprehensive fb-PMT safety assessments demonstrated excellent safety and tolerability at multiple folds above the anticipated human therapeutic doses. Lastly, our genome-wide microarray screens demonstrated that fb-PMT works through the molecular interference mechanism with multiple signaling pathways contributing to growth and survival of leukemic cells.ConclusionOur preclinical findings of the potent anticancer activities of fb-PMT and its favorable safety profiles warrant its clinical investigation for the effective and safe management of AML.

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Design, synthesis, and biological evaluation of bifunctional thyrointegrin inhibitors: new anti-angiogenesis analogs

Cited by 13 publications

References 71 publications

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin α_vβ₃ Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin α_vβ₃ Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme

Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvβ3 Receptors in the Treatment of Neuroblastoma

Targeting Thyrointegrin αvβ3 Using Fluorobenzyl Polyethylene Glycol Conjugated Tetraiodothyroacetic Acid (NP751) in Acute Myeloid Leukemia

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Design, synthesis, and biological evaluation of bifunctional thyrointegrin inhibitors: new anti-angiogenesis analogs

Cited by 13 publications

References 71 publications

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin αvβ3 Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin αvβ3 Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme

Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvβ3 Receptors in the Treatment of Neuroblastoma

Targeting Thyrointegrin αvβ3 Using Fluorobenzyl Polyethylene Glycol Conjugated Tetraiodothyroacetic Acid (NP751) in Acute Myeloid Leukemia

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Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin α_vβ₃ Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin α_vβ₃ Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme