Aurora A degradation by HSP90 interactome-mediating PROTACs in A549 and paclitaxel-resistant A549 cells

Lung cancer has one of the higher incidence and mortality rates worldwide. The development of drug resistance poses a significant challenge to lung cancer treatment. Aurora A kinase, a member of the Aurora family of proteins, has been identified as a key regulator of the cell cycle and mitotic spindle assembly, and overexpression is frequently observed in tumors. Kinase-independent oncogenic functions may be responsible for low clinical response rates, which are difficult to target the conventional small molecules. Targeting both the catalytic and non-catalytic functions of Aurora A may be a viable approach. In this study, we have designed and synthesized a series of novel Aurora A protein degradation-targeted chimeras (Aurora A-PROTACs) based on the HSP90 interactome. Unlike existing Aurora A PROTACs, the new AurAPs series utilizes HSP90, which is highly expressed in tumor cells, as the ligand to recruit the HSP90/E3 ubiquitin ligase complex. AurAPs induced the degradation of the target protein Aurora A by “hijacking” the HSP90/E3 complexes, effectively increasing the targeting of tumors. In vitro biochemical and cellular assays showed that AurAP14 effectively degraded Aurora A kinase, inhibited the proliferation of most human tumor cells and effectively attenuated the development of paclitaxel-resistant lung cancer cells. In addition, AurAP14 significantly inhibited the tumor growth of NSCLC and drug-resistant NSCLC xenograft tumor mice. The results from this study indicate that AurAP14 represents a promising delivery strategy for the sequential elimination of multiple functions of oncogenic proteins and the attenuation of chemotherapy-induced drug resistance.