Structural Superimposition

Abstact

Inhibition of several of the 10 hallmarks of cancer (Hanahan and Weinberg) would result in a broader and more durable treatment compared to current single or combination drug treatments. Galectin-1 and galectin-3 have been proposed to together be involved in all 10 hallmarks, suggesting that development of a combined galectin-1/3 inhibitor would be beneficial. Specificity toward galectin-1 or -3 can be modulated using different aryl moieties in 3-(aryl)triazolyl-galactopyranoside derivatives. By combining these findings, a new class of 3-(halothiazolyl)triazolyl derivatives with high affinity for both human galectin-1 and -3 were discovered and optimized with respect to SAR and in vitro ADME parameters, resulting in GB1841 (K(d) galectin-1/-3 0.027/0.14 muM). Both selective and dual inhibition of galectin-1 and galectin-3 significantly reduces the growth of LL/2 lung cancer cells in a syngeneic mouse model, supporting further development of GB1841 as a dual inhibitor of galectin-1 and galectin-3.