VH-298

A cell-permeant inhibitor of VHL

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Background

VH-298 is a highly potent inhibitor of the VHL:HIF-α interaction with a Kd value of 80 to 90 nM, used in PROTAC technology.

VH-298 is a potent, cell permeable and non-toxic chemical probe that triggers the hypoxic response by blocking the VHL. VH-298 is a highly potent inhibitor of the VHL:HIF-α interaction with Kd values of 90 and 80 nM in isothermal titration calorimetry and competitive fluorescence polarization assay. VH-298 binds with VHL complex very fast and dissociates slowly. VH-298 at 50 uM concentration exhibits negligible off-target effects in vitro against more than 100 tested cellular kinases, GPCRs and ion channels. VH-298 is cell permeable and not toxic to cells. The measured permeability of VH-298 is found to be 19.4 nm s -1. VH-298 induces concentration- and time-dependent on-target specific accumulation of hydroxylated HIF-α in human cell lines, including HeLa cancer cells and renal cell carcinoma 4 (RCC4) cells. VH-298 increases mRNA levels of EPO by 2.5-fold in RCC4-HA-VHL, but not in VHL-null RCC4-HA, indicating that pharmacological inhibition of VHL is able to stimulate endogenous EPO synthesis. VH-298 proves as effective as hypoxia in raising PHD2 and HK2 protein levels, however in HFF the BNIP3 protein level increases more with VH-298 treatment than hypoxia treatment[1].

参考文献:
[1]. Frost J, 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.

Protocol

Kinase experiment:

VH-298 is screened at 50 μM concentration against a panel of 50 kinases. The remaining kinase activity is recorded in the end of the assay. The data is reported as average % activity remaining of assay duplicates for each kinase tested[1].

Cell experiment:

Death of CTLs is analyzed by staining with 4′,6-diamidino-2-phenylindole (DAPI). Cells are plated in 96-well plates at 1×106 and treated with VHL inhibitors (VH-298) and respective non-binding cis-analogues for 24?h. Cells are spun down and resuspended in HBSS containing DAPI to identify dead and dying populations[1].

参考文献:

[1]. Frost J, 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.