LOX-1 inhibitor | BI-0115
Highlights
BI-0115 is a highly selective inhibitor of Lectin-like ox-LDL receptor 1 (LOX-1). This mechanism is mediated by stabilizing a protein-protein interaction. It has shown an acceptable in vitro profile with a clear inhibition of oxLDL internalization. This chemical probe may be a valuable tool to study LOX-1-mediated signal transduction pathways and cellular effects in different pathogenic pathways.
Background information
Target Information
Elevated plasma levels of oxidized low-density lipoproteins (oxLDL) play a role in proatherogenic processes like plaque formation and destabilization that are postulated to affect cardiovascular health negatively.2 Lectin-like ox-LDL receptor 1 (LOX-1) is the major cell surface receptor for oxLDL in a wide variety of different cell types and binds to and internalizes oxLDL, which leads to plaque formation in arteries.3,4 It is a 273 amino acid long Type II membrane protein with a short N-terminal intracellular region followed by the transmembrane domain. On the extracellular side, the long neck domain is predicted to be a long alpha helix ending in the C-terminal C-type lectin-like domain (CTLD). LOX-1 is a constitutively dimeric protein mediated via an inter chain disulphide bridge at Cys140.5,6,7 Oligomerization of LOX-1 receptors is an important step and regulated via the neck domain. It has been proposed that a complex of three LOX-1 dimers is needed to ligand ox-LDL and then internalize it via vascular endothelial cells.8,9
Stabilization of a LOX-1 receptor tetramer by two molecules of BI-0115 (PDB code 6TL9).1
In vitro activity
BI-0115 shows an IC50 potency of 5.4 µM in the LOX-1 cellular uptake assay. This compares well with a Kd value of 4.3 µM in surface plasmon resonance (SPR) and a Kd of 6.99 µM in isothermal titration calorimetry (ITC).1 To exclude unspecific and non-target related mechanisms, scavenger receptor class B type I (SR-BI), an alternative scavenger receptor with low sequence and structural homology to human LOX-1, has been used as counter target. BI-0115 shows no activity up to 100 µM in this assay.1
| Probe name / negative control | BI-0115 | BI-1580 |
| MW [Da] | 287.75 | 267.14 |
| LOX-1 (IC50) [µM]a | 5.4 | >100 |
| SR-B1 (IC50) [µM]a | >172 | >100 |
| SPR (Kd) [µM]a | 4.3 | NA |
| ITC (Kd) [µM]a | 6.99 | NA |
a For a detailed description of the LOX-1, SR-B1, SPR, and ITC assays, please refer to reference 1. For any additional questions, please reach out to the opnMe team using the Contact form.
In vitro DMPK and CMC parameters
BI-0115 displays a moderate solubility at pH 7 and a moderate permeability. Its stability in human, rat and mouse liver microsomes is not optimal, qualifying the compound primarily as an in vitro tool.1 BI-0115 has a good selectivity against the hERG channel (IC50 > 10 µM).
| Probe name / negative control | BI-0115 | BI-1580 |
| Solubility @ pH 7 [µg/ml] | 0.001 | NA |
| clogP | 3.6 | 2.8 |
| PAMPA permeability [cm/s] | 1.5 x 10-6 | NA |
| Microsomal stability (h/r/m) [% QH] | 77/95/95 | NA |
| hERG (IC50) [µM] | >10 | NA |
Negative control
 BI-1580 white.png)
BI-1580 serves as a negative control.
Selectivity
BI-0115 has a clean Eurofins Safety Panel 44™ profile and it shows no hERG channel inhibition. The selectivity of BI-0115 versus other paralogues of the C-type lectin-like family has not been tested.
| SELECTIVITY DATA AVILABLE | BI-0115 | BI-1580 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Co-crystal structure of the BI probe compound and the target protein
The X-ray structure of LOX-1 in complex with BI-0115 is available via PDB code 6TL9.1
Reference molecule(s)
Please see references 10 – 12.
Summary
BI-0115 is a highly selective in vitro molecule that inhibits LOX-1 and prevents internalization of oxLDL.
Supplementary data
2 D structure formats available
LOX-1 inhibitor | BI-0115.smiles
Negative Control | BI-1580.png
References
A small-molecule inhibitor of lectin-like oxidized LDL receptor-1 acts by stabilizing an inactive receptor tetramer state
Schnapp G., Neubauer H., Büttner F. H., Handschuh S., Lingard I., Heilker R., Klinder K., Prestle J., Walter R., Wolff M., Zeeb M., Debaene F., Nar H., Fiegen D.
CommsChem 2020; 3:75.
open accessCrystal structure of human lectin-like, oxidized low-density lipoprotein receptor 1 ligand binding domain and its ligand recognition mode to OxLDL
Ohki I., Ishigaki T., Oyama T., Matsunaga S., Xie Q., Ohnishi-Kameyama M., Murata T., Tsuchiya D., Machida S., Morikawa K., Tate S.
Structure 2005 Jun;13(6):905-17.
Oligomerization is required for the activity of recombinant soluble LOX-1
Cao W., Calabro V., Root A., Yan G., Lam K., Olland S., Sanford J., Robak A., Zollner R., Lu Z., Ait-Zahra M., Agostinelli R., Tchistiakova L., Gill D., Harnish D., Paulsen J., Shih H. H.
FEBS J. 2009 Sep;276(17):4909-20.
How to cite opnMe?
When you plan a publication, please use the following acknowledgement:
BI-0115 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://opnme.com.
Papers with our molecules. Published by you.
Cell-free Hemoglobin-Oxidized LDL Axis Contributes to Microvascular Endothelial Barrier Dysfunction and Poor Outcomes During Sepsis
Meegan J. E., Tomasek T., Desco A., Ware L. B., Bastarache J. A.
The FASEB Journal 2022, Vol. 36, No. 1. open access.
LOX-1 acts as an N6-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase
Zeng J., Xie C., Huang Z., Cho C. H., Chan H., Li Q., Ashktorab H., Smoot D. T., Wong S. H., Yu J., Gong W., Liang C., Xu H., Chen H., Liu X., Wu J. C. Y., Ip M., Gin T., Zhang L., Chan M. T. V., Hu W., Wu W. K. K.
Nat Commun. 2024, 15(1):669.
