Dual Vanin Inhibitor
BI-4122
BI-4122 is an orally available small molecule inhibitor that blocks in a reversible, competitive manner the enzymatic activities of vanin 1 and 2, and therefore potently inhibits the conversion of pantetheine into pantothenic acid and cysteamine.
More information
Vanin 1 and vanin 2 are single-domain enzymes tethered to the extracellular surface by a glycosylphosphatidylinositol (GPI)-linker but is also shed in from the cell surface into the extracellular milieu. The vanin enzymes function to convert pantetheine into pantothenic acid and cystamine, which is then reduced to cysteamine. Vanin 1 is expressed in immune-competent tissues as well as in intestine, liver, and kidney. Vanin 2 expression is detectable in most tissues with highest expression in spleen, kidney, and blood1.
The vanin enzymes regulate cellular redox homeostasis, as its reaction products are capable of interfering with glutathione biosynthesis. Studies in vanin 1 knockout mice have shown that the knockout animals were more resistant to oxidative stress and showed a lower inflammatory response compared with their wild-type littermates following challenge with different injury triggers2. In addition, vanin 1 knockout mice are resistant to inflammatory bowel disease3 and the vanins have been postulated to play potential roles in other disorders including malaria susceptibility4, psoriasis, colitis-associated colon cancer, and post-arterial injury neointimal hyperplasia based on preclinical evidence5-7.
BI-4122 is a small molecule compound that potently inhibits vanin enzymatic activity in mice and humans with nanomolar potency. It possesses a very favorable selectivity profile and DMPK properties, allowing standard oral application in dose response in vivo studies.
Model of the binding mode of BI-4122 in complex with vanin based on the X-ray structure with a closely related ligand
The orally bioavailable small molecule BI-4122 inhibits the enzymatic activity of vanin 1 and vanin 2 with IC50 of 0.3 and 1.5 nM biochemical potency and 2 nM in a human whole blood assay. The compound is also potently inhibiting vanin enzymatic activity of mouse and rat, making it a suitable tool for model investigations in these species.
| Probe name / Negative control | BI-4122 | BI-9534 |
| MW [Da]a | 344.42 | 420.50 |
| Human vanin 1 (IC50) [nM]b | 0.3 | 129.7 |
| Human vanin 2 (IC50) [nM]b | 11.0 | n.a. |
| Vanin human whole blood (IC50) [nM]c | 6.3 | n.a. |
a The molecule is supplied in salt form; for the molecular weight of the salt, please refer to the vial label.
b Enzymatic activity of vanin was evaluated by using D-Pantethine as a substrate and quantifying the production of pantothenic acid via label-free RapidFire mass spectrometry8.
c Enzymatic conversion of D-Pantethine into pantothenic acid in human whole blood was quantified using RapidFire mass spectrometry8.
BI-4122 has good solubility in water at all pH values. It shows high permeability in Caco-2 assay but significant efflux in the MDCK permeability assay.
| Probe name / Negative control | BI-4122 | BI-9534 |
| logD @ pH 7.4, clogD @ pH 7.4 | 0.0, 0.7 | n.a., 2.3 |
| Solubility @ pH 7 [µg/mL] | >1,000 | 69 (aqueous phase buffered) |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 13.3 | 14 |
| Caco-2 efflux ratio | 1.5 | 3.6 |
| MDCK permeability PappAB @ 1µM [10-6 cm/s] | 1.3 | 2.3 |
| MDCK efflux ratio | 13 | 33.5 |
| Microsomal stability (human/mouse/rat) [% QH] | <23 / <26 / <23 | 76 / 81 / 84 |
| Hepatocyte stability (human/mouse/rat) [% QH] | 2 / 7 / 18 | n.a. / 91 / 90 |
| Plasma protein binding (human/mouse/rat) [%] | 13.3 / 26.3. / 16.1 | 78.7 / 70.3 / 65.4 |
| hERG (IC50) [µM] | >100 | >30 |
| CYP 3A4 (IC50) [µM] | >50 | >50 |
| CYP 2C8 (IC50) [µM] | >50 | n.a. |
| CYP 2C9 (IC50) [µM] | >50 | n.a. |
| CYP 2C19 (IC50) [µM] | >50 | 45.8 |
| CYP 2D6 (IC50) [µM] | >50 | >50 |
| CYP 1A2 (IC50) [µM] | >50 | >50 |
| CYP 2B6 (IC50) [µM] | >50 | >50 |
Pharmacokinetic (PK) properties support an i.v. application. In addition, in rodent animal species (rats) administration is suitable for once or twice daily oral dosing in acute or sub-chronic in vivo experiments.
| BI-4122 | Mouse | Rat |
| Clearance [% QH]a | 32.6 | 35.8 |
| Mean residence time after i.v. dose [h]a | 0.6 | 3.2 |
| tmax [h]b | n.a. | 0.3 |
| Cmax [nM]b | n.a. | 11,025 |
| F [%]b | n.a. | 44 |
| Vss [L/kg]a | 1.1 | 4.7 |
a i.v. dose: mouse: 1 mg/kg, rat: 1mg/kg
b p.o. dose: mouse: n.a., rat: 3 mg/kg
BI-9534, a structurally close analog, can be used as negative control.
BI-9534 which serves as a negative control
BI-4122 shows no significant activity in a panel of 268 kinases and 68 enzymes/receptors tested at 10 µM. BI-9534 inhibited only one target (COX-1@CE) with > 50% at a 10µM in the SafetyScreen44™.
| SELECTIVITY DATA AVILABLE | BI‑4122 | BI‑9534 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | Yes | No |
Download selectivity data:
BI-4122_selectivityData.xlsx
BI-9534_selectivityData.xlsx
Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptor gamma activity
Berruyer C., Pouyet L., Millet V., Martin F. M., LeGoffic A., Canonici A., Garcia S., Bagnis C., Naquet P., Galland F.
J Exp Med 2006, 203(13), 2817–2827.
Expression of the vanin gene family in normal and inflamed human skin: Induction by proinflammatory cytokines
Jansen P. A. M., Kamsteeg M., Rodijk-Olthuis D., van Vlijmen-Willems I. M. J. J., Jongh G. J. de, Bergers M., Tjabringa G. S., Zeeuwen P. L. J. M., Schalkwijk J.
J Invest Dermatol 2009, 129(9), 2167–2174.
Heteroaromatic compounds as Vanin Inhibtitors
Doe, J., Smith, J.
WIPO 2018, (Patent No. WO2018/228934).
When you plan a publication, please use the following acknowledgement:
BI-4122 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.