New Thyrointegrin alpha(v)beta(3) Antagonist with a Scalable Synthesis, Brain Penetration, and Potent Activity against Glioblastoma Multiforme

We have previously reported that the alpha(v)ss(3) inhibitor P-bi-TAT, a bifunctional version of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) conjugated to polyethylene glycol (PEG) MW 4000, has excellent efficacy in a glioblastoma multiforme (GBM) mouse model. However, bioanaly...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 64; no. 9; pp. 6300 - 6309
Main Authors Hay, Bruce A., Godugu, Kavitha, Darwish, Noureldien H. E., Fujioka, Kazutoshi, Sudha, Thangirala, Karakus, Ozlem Ozen, Mousa, Shaker A.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 13.05.2021
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
PROTEIN
PHARMACOKINETICS
ANGIOGENESIS
THYROID-HORMONE
NEWLY-DIAGNOSED GLIOBLASTOMA
INTEGRIN ALPHA(V)BETA
CANCER
CILENGITIDE
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Summary:We have previously reported that the alpha(v)ss(3) inhibitor P-bi-TAT, a bifunctional version of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) conjugated to polyethylene glycol (PEG) MW 4000, has excellent efficacy in a glioblastoma multiforme (GBM) mouse model. However, bioanalysis problems due to PEG polydispersity and large-scale synthesis issues led to a search for new molecules, culminating in the discovery of fb-PMT, a conjugate of tetrac and monodisperse PEG36, with a lipophilic 4-fluorobenzyl group at the opposite end of the PEG chain. fb-PMT reduces GBM tumor growth and viability by up to 98%, is suitable for large-scale synthesis, and is amenable to bioanalysis using mass spectrometry-based detection. We also showed that changes in lipophilicity at the opposite end of the PEG chain from the active tetrac component affected the proton NMR chemical shift of the tetrac moiety in D(2)0 and brain levels of the compound after subcutaneous dosing.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00350