VH-298 is a selective VHL (Von Hippel-Lindau) inhibitor (Kd=80-90nM). VH-298 stabilizes HIF-α proteins and triggers a hypoxic response by blocking the interaction between VHL and HIF-α proteins. VH-298 can be used in PROTAC (Proteolysis Targeting Chimera) technology and research related to hypoxia signaling pathways[1-4].
In vitro, VH-298 (30-100μM) was used to treat CD4⁺ T cells under Th17-polarizing conditions for 72 hours. VH-298 increased HIF-1α protein levels, simultaneously upregulated IL-17 and GLUT1 expression, and partially restored Th17 cell differentiation[5]. VH-298 (50μM) was used to treat HeLa cells and RPE/mRFP-EGFP-SKL cells for 48 hours. VH-298 significantly promoted peroxisomal degradation (pexophagy), increased ABCD3 ubiquitination, and activated HIF-1α[6].
In vivo, VH-298 (30μM; 100μl; every three days) was locally injected into the wound area of hyperglycemic rats for 21 days. VH-298 improved wound healing, activated the HIF-1 signaling pathway, and promoted vascularization in rats[7]. VH-298 (30μM; 100μl; daily) was injected into the reconstructed attachment site area of a Sprague-Dawley rat model with Achilles tendon-calcaneus rupture. VH-298 improved Achilles tendon-calcaneus healing, increased maximum load and failure energy, and activated the HIF signaling pathway in rats[8].
References:
[1] Frost J, Galdeano C, Soares P, et al. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nat Commun. 2016 Nov 4;7:13312.
[2] Ling J, Chen H, Huang M, et al. An mRNA vaccine encoding proteasome-targeted antigen enhances CD8+ T cell immunity. J Control Release. 2025 May 10;381:113578.
[3] Wang Y, Cao Z, Wei Q, et al. VH298-loaded extracellular vesicles released from gelatin methacryloyl hydrogel facilitate diabetic wound healing by HIF-1α-mediated enhancement of angiogenesis. Acta Biomater. 2022 Jul 15;147:342-355.
[4] Qin X, Wu K, Zuo C, et al. The Expression and Role of Hypoxia-induced Factor-1α in Human Tenon's Capsule Fibroblasts under Hypoxia. Curr Eye Res. 2021 Mar;46(3):417-425.
[5] Zhang Q, Wang L, Jiang J, et al. Critical Role of AdipoR1 in Regulating Th17 Cell Differentiation Through Modulation of HIF-1α-Dependent Glycolysis. Front Immunol. 2020 Aug 18;11:2040.
[6] Kim YH, Park NY, Jo DS, et al. Inhibition of VHL by VH298 Accelerates Pexophagy by Activation of HIF-1α in HeLa Cells. Molecules. 2024 Jan 18;29(2):482.
[7] Qiu S, Jia Y, Sun Y, et al. Von Hippel-Lindau (VHL) Protein Antagonist VH298 Improves Wound Healing in Streptozotocin-Induced Hyperglycaemic Rats by Activating Hypoxia-Inducible Factor- (HIF-) 1 Signalling. J Diabetes Res. 2019 Feb 17;2019:1897174.
[8] Qiu S, Jia Y, Tang J, et al. Von Hippel-Lindau (VHL) protein antagonist, VH298, promotes functional activities of tendon-derived stem cells and accelerates healing of entheses in rats by inhibiting ubiquitination of hydroxy-HIF-1α. Biochem Biophys Res Commun. 2018 Nov 10;505(4):1063-1069.