| Bioactivity | 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. | ||||||||||||
| Target | Kd: 80 to 90 nM (VHL:HIF-α) | ||||||||||||
| Invitro | 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 μM 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]. | ||||||||||||
| Name | VH-298 | ||||||||||||
| CAS | 2097381-85-4 | ||||||||||||
| Formula | C27H33N5O4S | ||||||||||||
| Molar Mass | 523.65 | ||||||||||||
| Appearance | Solid | ||||||||||||
| Transport | Room temperature in continental US; may vary elsewhere. | ||||||||||||
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| Reference | [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. |