N-(4,5,6,7-tetrahydrobenzo[d]isoxazol-5-yl)carboxamides as potential anticancer agents targeting HSP90 and oncogenic kinases

Abstract

Modulation of the molecular chaperone HSP90 represents a promising therapeutic strategy in oncology. As a continuation of our research aimed at designing new HSP90 modulators based on the 6,7-dihydrobenzo[d]isoxazol-4(5H)-one scaffold, we established a strategy for the synthesis of a novel class of compounds: N- (4,5,6,7-tetrahydrobenzo[d]isoxazol-5-yl)carboxamides. A series of such substances was synthesized and evaluated for antiproliferative activity against breast cancer cell lines. Several compounds exhibited potent activity in the low micromolar to submicromolar range. The lead molecule, 5c, demonstrated an IC 50 of 0.45 μM in HER2+ HCC1954 cells, where it effectively suppressed the expression of HER2 and p-HER2, as well as p-c-MET and p-EGFR. The results suggest a dual mechanism of action, involving both HSP90 modulation and direct inhibition of oncogenic kinases, as supported by molecular docking and molecular dynamics studies. Moreover, the potential of compound 5c in combination with established antiproliferative agents was assessed in a cellular model, highlighting its translational relevance. Collectively, our results identify N- (4,5,6,7-tetrahydrobenzo[d]isoxazol-5yl)carboxamides as a promising class of multitarget anticancer agents, providing a foundation for the development of next-generation inhibitors acting on both HSP90 and oncogenic kinases.