Cathepsin S inhibitor
BI-1915
BI-1915 is a highly potent inhibitor of Cathepsin S (CatS) (IC50 = 17 nM). It shows excellent selectivity against related cathepsins (> 500-fold). BI-1915 was shown to effectively block the specific secretion of ovalbumin-induced IL-2 in T-cells. This compound is suitable for in vitro experiments.
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Cathepsin S is a 24 kD lysosomal cysteine protease that plays a pivotal role in antigen processing and presentation, which are important processes in normal immune responses and autoimmunity.
Human Cathepsin S in complex with an analog of BI-1915 (PDB Code: 2R9M)1
The in vitro molecule BI-1915 and the in vivo compound BI-1124 are both highly potent inhibitors of Cathepsin S with IC50 values of 17 nM and 7 nM, respectively. BI-1920 does not inhibit Cathespin S (IC50 > 20µM) and can serve as a structurally related negative control for in vitro experiments.
Both tools effectively block the specific ovalbumin induced IL-2 secretion in T-cells with EC50 values of 2.8 nM and 0.5 nM, respectively. Furthermore, BI-1124 has a superior PK profile and showed dose-dependent inhibition of the ovalbumin induced IL-2 secretion in a T cell receptor transgenic DO11 mouse model with and IC50 of 0.3 mg/kg.
in vitro compound BI-1915 shows excellent selectivity (>500 fold) against related cathepsins with IC50 values of >10 µM (Cat K and Cat B) and >30 µM (Cat L), and also the in vivo tool BI-1124 shows good selectivity (>40 fold) against Cat K, B, and L.
| Probe names / negative control | BI-1915 | BI-1124 | BI-1920 |
| MW (free base) [Da]a | 407.6 | 407.6 | 365.5 |
| Binding to Cathepsin S (KD) [µM]b | 0.031 | 0.009 | 272 |
| Inhibition of Cathepsin S (IC50) [µM]b | 0.017 | 0.007 | >20 |
| Antigen challenge cell assay (IC50) [nM]c | 2.8 | 0.5 | n.d. |
| Cathepsin L IC50 [µM] | >30 | 0.29 | n.d. |
| Cathepsin K IC50 [µM] | >10 | 0.35 | n.d. |
| Cathepsin B IC50 [µM] | >10 | 6.8 | n.d. |
aFor the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
bDetermined by SPR
cFor assay conditions see reference 7, supplementary data.
| Probe name / negative control | BI-1915 | BI-1124 | BI-1920 |
| logD @ pH 11 | 1.8 | n.a. | n.a. |
| Solubility @ pH 7.4 [µg/ml] | 1.7 mg/mL | >0.3 mg/mL | n.a. |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 1.7 | 0.7 | n.a. |
| Caco-2 efflux ratio | 4.1 | 16.2 | n.a. |
| Microsomal stability (human/mouse/rat) [% QH] | 60 / 72 / 31 | <24 / n.d. / n.d. | <11/ n.d. / n.d. |
| Plasma protein binding (human) [%] | 26 | n.a. | n.a. |
| hERG IC50 [µM] | >300 | n.a. | n.a. |
| CYP 3A4 (IC50) [µM] | n.a. | >50 | n.a. |
| CYP 2C9 (IC50) [µM] | n.a. | >50 | n.a. |
| CYP 2D6 (IC50) [µM] | n.a. | >50 | n.a. |
BI-1920 offered as negative control with low binding affinity to Cathepsin S (KD 270 µM) and an IC50 for the inhibition of Cathepsin S of >20µM.
BI-1920 which serves as a negative control
| SELECTIVITY DATA AVILABLE | BI-1915 | BI-1920 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-1915_selectivityData2.xlsx
BI-1920_selectivityData_0.xlsx
The Xray crystal structure of Cathepsin S in complex with an analog of BI-1915 is available (PDB code: 2R9O, Reference 1).
See reference 6.
BI-1915 is a highly potent inhibitor of Cathepsin S (IC50 17 nM) with excellent selectivity against related cathepsins and is therefore a valuable tool for in vitro experiments.
Design and Synthesis of Dipeptide Nitriles as Reversible and Potent Cathepsin S Inhibitors
Ward Y. D., David S., Thomson D. S., Frye L. L., Cywin C. H., Morwick T., Emmanuel M. J., Zindell R., McNeil D., Bekkali Y., Hrapchak M., DeTuri M., Crane K., White D., Pav S., Wang Y., Hao M.-H., Grygon C. A., Labadia M. E., Freeman D.M., Davidson W., Hopkins J. L., Brown M. L. and Spero D. M.
J. Med. Chem. 2002, 45, 5471-5482.
Identification of a novel class of succinyl-nitrile-based Cathepsin S inhibitors
Bekkali Y., Thomson D. S., Betageri R., Emmanuel M. J., Hao M. H., Hickey E., Liu W., Patel U., Ward Y. D., Young E. R., Nelson R, Kukulka A., Brown M. L., Crane K., White D., Freeman D. M., Labadia M. E., Wildeson J., Spero D. M.
Bioorg. Med. Chem. Lett. 2007, 17, 2465-2469.
Exploration of cathepsin S inhibitors characterized by a triazole P1-P2 amide replacement
Moss N., Xiong Z., Burke M., Cogan D., Gao D.A., Haverty K., Heim-Riether A., Hickey E. R., Nagaraja R., Netherton M., O'Shea K., Ramsden P., Schwartz R., Shih D.T., Ward Y., Young E., Zhang Q.
Bioorg. Med. Chem. Lett. 2012, 22, 7189-7193.
When you plan a publication, please use the following acknowledgement:
BI-1915 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.