Repurposing AS1411 for constructing ANM-PROTACs

Xuekun Fu; Jin Li; Xinxin Chen; Hongzhen Chen; Zhuqian Wang; Fang Qiu; Duoli Xie; Jie Huang; Siran Yue; Chunhao Cao; Yiying Liang; Aiping Lu; Chao Liang

doi:10.1016/j.chembiol.2024.03.011

Repurposing AS1411 for constructing ANM-PROTACs

Cell Chem Biol. 2024 Apr 12:S2451-9456(24)00127-2. doi: 10.1016/j.chembiol.2024.03.011. Online ahead of print.

Authors

Xuekun Fu¹, Jin Li², Xinxin Chen², Hongzhen Chen², Zhuqian Wang¹, Fang Qiu¹, Duoli Xie¹, Jie Huang¹, Siran Yue¹, Chunhao Cao¹, Yiying Liang³, Aiping Lu⁴, Chao Liang⁵

Affiliations

¹ Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China; Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China.
² Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
³ Shenzhen LingGene Biotech Co., Ltd, Shenzhen 518055, China.
⁴ Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou 510006, China; Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: aipinglu@hkbu.edu.hk.
⁵ Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China; Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China; State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China. Electronic address: liangc@sustech.edu.cn.

PMID: 38657608
DOI: 10.1016/j.chembiol.2024.03.011

Abstract

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands joined by a linker, enabling them to simultaneously bind with an E3 ligase and a protein of interest (POI) and trigger proteasomal degradation of the POI. Limitations of PROTAC include lack of potent E3 ligands, poor cell selectivity, and low permeability. AS1411 is an antitumor aptamer specifically recognizing a membrane-nucleus shuttling nucleolin (NCL). Here, we repurpose AS1411 as a ligand for an E3 ligase mouse double minute 2 homolog (MDM2) via anchoring the NCL-MDM2 complex. Then, we construct an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) by conjugating AS1411 with large-molecular-weight ligands for "undruggable" oncogenic STAT3, c-Myc, p53-R175H, and AR-V7. We show that the ANM-PROTAC efficiently penetrates tumor cells, recruits MDM2 and degrades the POIs. The ANM-PROTAC achieves tumor-selective distribution and exhibits excellent antitumor activity with no systemic toxicity. This is a PROTAC with built-in tumor-targeting and cell-penetrating capacities.

Keywords: AS1411; MDM2; PROTAC; TPD; cancer; transcription factor.