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Published on: May 14, 2018
Aurora A degradation by HSP90 interactome-mediating PROTACs in A549 and paclitaxel-resistant A549 cells
Xiao-Yi Deng1, Hao Xu1, Yi-Xuan Peng1
1State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
Abstract:
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.
Insights
New Aurora A PROTACs (AurAPs) target cancer cells by degrading Aurora A kinase. AurAP14 shows promise in inhibiting lung cancer proliferation and overcoming drug resistance in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Lung cancer presents high incidence and mortality globally, with drug resistance complicating treatment.
- Aurora A kinase, overexpressed in tumors, regulates cell cycle and mitosis; its kinase-independent functions contribute to poor treatment response.
- Conventional small molecules struggle to target all Aurora A functions, necessitating novel therapeutic strategies.
Purpose of the Study:
- To design and synthesize novel Aurora A protein degradation-targeted chimeras (PROTACs) targeting both catalytic and non-catalytic functions.
- To utilize HSP90 as a ligand to recruit E3 ubiquitin ligase complexes for Aurora A degradation.
- To evaluate the efficacy of a lead compound, AurAP14, against lung cancer and drug-resistant models.
Main Methods:
- Design and synthesis of Aurora A-PROTACs (AurAPs) leveraging the HSP90 interactome.
- In vitro biochemical and cellular assays to assess Aurora A degradation and anti-proliferative effects.
- In vivo studies using NSCLC xenograft mouse models, including drug-resistant variants.
Main Results:
- AurAP14 effectively degraded Aurora A kinase in vitro.
- AurAP14 inhibited proliferation in various human tumor cells and attenuated paclitaxel-resistant lung cancer cells.
- AurAP14 significantly suppressed tumor growth in both NSCLC and drug-resistant NSCLC xenograft models.
Conclusions:
- The novel AurAP series, utilizing HSP90, effectively degrades Aurora A kinase.
- AurAP14 demonstrates significant anti-tumor activity and overcomes chemoresistance in preclinical lung cancer models.
- AurAP14 represents a promising strategy for targeting oncogenic proteins and enhancing chemotherapy efficacy.
