Cathepsin S inhibitor
BI-1124
BI-1124 is a highly potent inhibitor of the lysosomal cysteine protease Cathepsin S (IC50 = 7 nM). It shows good selectivity against the related cathepsins K, B and L (> 40-fold). BI-1124 has a PK profile superior to BI-1915 and shows effective dose-dependent inhibition of the specific secretion of ovalbumin-induced IL-2 in T-cells. This compound is suitable for in vivo studies.
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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-1124 (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 Cathepsin S (IC50 > 20µM) and can serve as a structurally related negative control for in vitro experiments.
Both molecules effectively block the specific ovalbumin induced IL-2 secretion in T-cells with EC50 values of 2.8 nM and 0.5 nM, respectively.
| 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]c | 0.017 | 0.007 | >20 |
| Antigen challenge cell assay (EC50) [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. |
a For 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
b Determined by SPR.
c For assay conditions see reference 7, supplementary data.
| Probe name / negative control | BI-1915 | BI-1124 | BI-1920 |
| logD @ pH11 | 1.8 | 2.5 | 1.0 |
| Solubility @ pH 7.4 [µg/mL] | 1.7 | 77.6 | n.a. |
| CACO-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 1.7 | 0.7 | n.a. |
| CACO efflux ratio | 4.1 | 16.2 | n.a. |
| Microsomal stability (human/mouse/rat) [% QH] | 60 / 72 / 31 | <24 / 52 / <22 | n.a./ n.a. / n.a. |
| 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 2C8 (IC50) [µM] | n.a. | n.a. | n.a. |
| CYP 2C9 (IC50) [µM] | n.a. | >50 | n.d. |
| CYP 2C19 (IC50) [µM] | n.a. | n.a. | n.a. |
| CYP 2D6 (IC50) [µM] | n.a. | >50 | n.a. |
BI-1124 | MOUSE |
| Clearance [%QH]a | 55 |
| Mean residence time after iv dose [h]a | 1.3 |
| Vss [l/kg]a | 3.8 |
| Cmax [nM]b | 370 |
| F [%] | 79 |
a i.v. dose: 0.4 mg/kg
b p.o. dose: 1.0 mg/kg
BI-1915 and BI-1124 were investigated in a T cell receptor transgenic DO11 mouse model in which the compounds were dosed orally followed by an i.v. antigen (ovalbumin) at 0.5 hour with a readout of plasma IL-2 at 3.5 hours.
BI-1915 and BI-1124 showed dose-dependent inhibition of the ovalbumin induced IL-2 secretion with an EC50 of 3 mg/kg and 0.3 mg/kg, respectively.
BI-1920 is offered as a 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
The in vivo tool BI-1124 shows good selectivity (>40 fold) against Cat K, B and L. The in vitro tool 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).
| SELECTIVITY DATA AVILABLE | BI-1124 | BI-1920 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-1124_selectivityData.xlsx
BI-1920_selectivityData_1.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-1124 is a highly potent inhibitor of the lysosomal cysteine protease Cathepsin S (IC50 7 nM) with a superior pharmacokinetic profile and good selectivity against Cat K, B, and L. It is suitable for in vivo use.
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-1124 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.