TY - JOUR
T1 - Design of Murine Double Minute 2 Proteolysis Targeting Chimera Degraders with a Built-In Tumor-Targeting Ability
AU - Wang, Zhuqian
AU - Yue, Siran
AU - Chen, Xinxin
AU - Li, Jin
AU - Zhu, Peixi
AU - Chen, Hongzhen
AU - Qiu, Fang
AU - Xie, Duoli
AU - Liang, Yiying
AU - Li, Defang
AU - Lu, Aiping
AU - Liang, Chao
N1 - Funding Information:
The authors acknowledge the assistance of Southern University of Science and Technology Core Research Facilities, the Experimental Animal Center of Southern University of Science and Technology. Schematic diagrams were created with BioRender.com. This work is supported by the National Natural Science Foundation Council of China (82472394 and 82172386 to C.L.), the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab) (2020B1212030006 to A.L.), the Guangdong Basic and Applied Basic Research Foundation (2022A1515012164 to C.L.), the Science, Technology, and Innovation Commission of Shenzhen (JCYJ20210324104201005 to C.L.), the Hong Kong General Research Fund (12102722 to A.L.), the Hong Kong RGC Theme-based Research Scheme (T12-201/20-R to A.L.), and the Shenzhen LingGene Biotech Co., Ltd.
Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/11/14
Y1 - 2024/11/14
N2 - Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules to induce the proteasomal degradation of target proteins. Currently, there are no tumor-targeting PROTACs for modulating oncogenic murine double minute 2 (MDM2). AS1411 is a tumor-targeting aptamer that specifically recognizes nucleolin (NCL) overexpressed on the surface of tumor cells. We recently repurposed AS1411 as an MDM2 recruiter since it could form an NCL-bridged ternary complex with MDM2. In this study, we design a PROTAC molecule AS1411-VH032 via conjugating AS1411 with a recruiter of von Hippel-Lindau (VHL) ligase VH032. AS1411-VH032 facilitates tumor-selective degradation of MDM2, leading to tumor shrinkage with no detectable toxicity. Besides being a molecular target, MDM2 also serves as an E3 ligase harnessed by PROTACs. Thus, we developed an AS1411-based homo-PROTAC homoAS1411, which induces tumor-specific suicide degradation of MDM2 and prevents tumor progression without causing side effects. Both AS1411-VH032 and homoAS1411 are promising MDM2 degraders with built-in tumor-targeting ability, which balances the antitumor efficacy with a favorable safety profile.
AB - Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules to induce the proteasomal degradation of target proteins. Currently, there are no tumor-targeting PROTACs for modulating oncogenic murine double minute 2 (MDM2). AS1411 is a tumor-targeting aptamer that specifically recognizes nucleolin (NCL) overexpressed on the surface of tumor cells. We recently repurposed AS1411 as an MDM2 recruiter since it could form an NCL-bridged ternary complex with MDM2. In this study, we design a PROTAC molecule AS1411-VH032 via conjugating AS1411 with a recruiter of von Hippel-Lindau (VHL) ligase VH032. AS1411-VH032 facilitates tumor-selective degradation of MDM2, leading to tumor shrinkage with no detectable toxicity. Besides being a molecular target, MDM2 also serves as an E3 ligase harnessed by PROTACs. Thus, we developed an AS1411-based homo-PROTAC homoAS1411, which induces tumor-specific suicide degradation of MDM2 and prevents tumor progression without causing side effects. Both AS1411-VH032 and homoAS1411 are promising MDM2 degraders with built-in tumor-targeting ability, which balances the antitumor efficacy with a favorable safety profile.
UR - http://www.scopus.com/inward/record.url?scp=85207336396&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.4c01228
DO - 10.1021/acs.jmedchem.4c01228
M3 - Journal article
C2 - 39437434
AN - SCOPUS:85207336396
SN - 0022-2623
VL - 67
SP - 18865
EP - 18882
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -