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J Med Chem ; 67(11): 9374-9388, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38804039

RESUMO

We have previously described a new series of selective and orally available galectin-1 inhibitors resulting in the thiazole-containing glycomimetic GB1490. Here, we show that the introduction of polar substituents to the thiazole ring results in galectin-1-specific compounds with low nM affinities. X-ray structural analysis of a new ligand-galectin-1 complex shows changes in the binding mode and ligand-protein hydrogen bond interactions compared to the GB1490-galectin-1 complex. These new high affinity ligands were further optimized with respect to affinity and ADME properties resulting in the galectin-1-selective GB1908 (Kd galectin-1/3 0.057/6.0 µM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC50 = 850 nM). Pharmacokinetic experiments in mice revealed that a dose of 30 mg/kg b.i.d. results in free levels of GB1908 in plasma over galectin-1 Kd for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model.


Assuntos
Antineoplásicos , Galectina 1 , Neoplasias Pulmonares , Galectina 1/antagonistas & inibidores , Galectina 1/metabolismo , Humanos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Administração Oral , Apoptose/efeitos dos fármacos , Relação Estrutura-Atividade , Células Jurkat , Descoberta de Drogas , Cristalografia por Raios X , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tiazóis/química
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