Thiadiazolo‐Triazolo‐Pyrimidine Hybrids as Dual Aurora A/ERK Inhibitors: Design, Synthesis, and Apoptotic Activity

ABSTRACT

Aberrant activation of Aurora A kinase causes mitotic spindle assembly, chromosome segregation, and cell cycle progression, leading to genomic instability as well as disruption of several tumor suppressors. Furthermore, ERK has largely emerged as a survival signaling pathway controlling cell proliferation, differentiation, and metastasis. Unfortunately, this pathway is overexpressed in most of the human malignancies. In efforts to develop innovative inhibitors targeting Aurora A/ERK signaling pathway, a novel series of thiadiazolo‐, triazolo‐pyrimidine hybrids have been designed, synthesized, and assessed for their ability to block Aurora A/ERK and induce apoptosis. Cytotoxicity of the synthesized hybrids was examined against MCF‐7, HCT‐116 and A549 cell lines. Among the synthesized hybrids, 9a , 9c , and 14b demonstrated higher cytotoxic action than alisertib and GDC‐0994 against the MCF‐7 and A549 cancer cell lines. IC ₅₀ values for these hybrids were 2.59 ± 0.13, 4.63 ± 0.25, and 5.77 ± 0.38, respectively, against MCF‐7 cell line and were 3.61 ± 0.19, 3.85 ± 0.21, and 4.23 ± 0.15, respectively, against A549. The selected hybrids significantly suppressed p‐Aurora A kinase level as well as p‐ERK1/2 level and its upstream regulators p‐SRC, p‐c‐RAF, p‐MEK1/2; meanwhile, ERK downstream effectors FOXO3a level was upregulated, and c‐Myc was downregulated, in a dose‐dependent manner. The selected hybrids significantly decreased the expression of Bcl‐2 protein while increasing the levels of p53 , caspase‐7, caspase‐9, and Bax. They effectively induced pre‐G1 phase, G0/G1 phase apoptosis, and G2/M phase arrest. The synthesized hybrids possessed favorable binding interactions in the molecular docking investigations as well as appropriate drug‐like characteristics.