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

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. (c) 2024 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.