PROTAC HK2 Degrader-1 is a proteolysis-targeting chimera (PROTAC) targeting hexokinase 2 (HK2), generated by conjugating the HK2 inhibitor Lonidamine with the CRBN E3 ubiquitin ligase ligand Thalidomide via a linker[1]. PROTAC HK2 Degrader-1 selectively degrades HK2 through the ubiquitin-proteasome system[2], leading to blocked glycolysis, mitochondrial damage, and immunogenic cell death, and is commonly used for the treatment and research of breast cancer[3,4,5].
In vitro, treatment with PROTAC HK2 Degrader-1 (0.1, 0.5, 1.25, 2.5, 5μM) for 72h in ES2 and ES2TR120 cells dose-dependently reduced cell viability, achieving maximal inhibitory effect at 1.25μM. Treatment with PROTAC HK2 Degrader-1 (1.25μM) for 48h in ES2TR120 cells significantly decreased the mitochondrial oxygen consumption rate (OCR)[6]. Treatment with PROTAC HK2 Degrader-1 (0.5μM) for 36h in HCAECs significantly reduced the elevation of lactate levels following stimulation with oxidized low-density lipoprotein (ox-LDL)[7].
In vivo, PROTAC HK2 Degrader-1 (5mg/kg; every other day) was administered via intraperitoneal injection to high-fat diet-fed ApoeKO mice for 12 weeks, significantly reducing the severity of atherosclerotic lesions[7].
References:
[1] Sang R, Fan R, Deng A, et al. Degradation of hexokinase 2 blocks glycolysis and induces GSDME-dependent pyroptosis to amplify immunogenic cell death for breast cancer therapy[J]. Journal of Medicinal Chemistry, 2023, 66(13): 8464-8483.
[2] Huang H, Deng A, Pan F, et al. PROTAC-mediated regulation of programmed cell death: From molecular mechanisms to therapeutic breakthroughs[J]. The Innovation, 2026.
[3] Chao Y L, Wang S, Luo L, et al. HIF-1α exerts a double-edged sword regulatory role in hippocampal neuronal PANoptosis of Alzheimer's disease through HK2/VDAC1/NLRP3 axis and RIPK3 signal[J]. 2025.
[4] Gao H, He Z, Chen J, et al. Macrocyclic Peptide-Based Dual-Sensor Platform for Linkage-Specific Visualization of Ubiquitin Chain Assembling in Live Cells[J]. Analytical Chemistry, 2025, 97(4): 2351-2358.
[5] Zhang T, Zhou W, Fan T, et al. Lactic acid metabolism: gynecological cancer's Achilles’ heel[J]. Discover Oncology, 2025, 16(1): 657.
[6] Lin T Y, Gu S Y, Lin Y H, et al. Paclitaxel-resistance facilitates glycolytic metabolism via Hexokinase-2-regulated ABC and SLC transporter genes in ovarian clear cell carcinoma[J]. Biomedicine & Pharmacotherapy, 2024, 180: 117452.
[7] Dong M, Zhang Y, Chen M, et al. ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT[J]. Acta Pharmaceutica Sinica B, 2024, 14(7): 3027-3048.