Citation: Yang Liu, Yan Liu, Kaiyin Yang, Zhiruo Zhang, Wenbo Zhang, Bingyou Yang, Hua Li, Lixia Chen. A selective HK2 degrader suppresses SW480 cancer cell growth by degrading HK2[J]. Chinese Chemical Letters, ;2024, 35(8): 109264. doi: 10.1016/j.cclet.2023.109264 shu

A selective HK2 degrader suppresses SW480 cancer cell growth by degrading HK2

Yang Liu ^{a, 1} ,
Yan Liu ^{b, 1} ,
Kaiyin Yang ^{d, 1} ,
Zhiruo Zhang ^a ,
Wenbo Zhang ^a ,
Bingyou Yang ^{b, *,} ,
Hua Li ^{a, c, *,} ,
Lixia Chen ^{a, *,}

a.
Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
b.
Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin 150006, China
c.
Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
d.
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

ybywater@163.com

2022041@fjtcm.edu.cn

syzyclx@163.com

Received Date: 29 August 2023
Revised Date: 29 October 2023
Accepted Date: 30 October 2023
Available Online: 3 November 2023

Figures(4)

Hexokinase 2 (HK2) is the rate-limiting enzyme in the first step of glycolysis, catalyzing glucose to glucose-6-phosphate, and overexpressed in most cancer cells. HK2 also binds to voltage-dependent anion channel (VDAC) to stabilize the mitochondrial outer membrane, which inhibits cancer cell apoptosis. Therefore, HK2 has become a potential target for cancer treatment. Proteolysis targeting chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent and specific PROTACs targeting dissimilar targets have been developed. In this study, an HK2 PROTAC, 4H-5P-M, was developed and induced the degradation of HK2 relying on the ubiquitin-proteasome system. It was found that 4H-5P-M as an effective HK2 degrader induced HK2 degradation in a dose- and time-dependent manner and suppressed the growth of SW480 cells. 4H-5P-M selectively induced HK2 degradation at a lower concentration than other hexokinase isozymes. Moreover, it could suppress glycolysis and accelerate the apoptosis of cancer cells. Therefore, it provided a new insight into the development of anti-tumor drugs.
- HK2,
- PROTACs,
- Degrader,
- Anti-tumor,
- SW480
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