CCR10 antagonist | BI-6901
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Highlights
BI-6901 is the first small molecule inhibitor of the chemokine receptor CCR10.1-3 The racemate of BI-6901 shows consistent potency in assays with various functional readouts and across different cell backgrounds. No meaningful binding or activity was observed against 29 GPCR’s, including 6 chemokine receptors. Although BI-6901 has a high clearance it was a suitable compound for in vivo validation. It is efficacious in a murine model of DNFB contact hypersensitivity.1
We also offer the optical antipode (BI-6902) as negative control which was inactive in the in vivo model.1
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Target information
“The chemokine receptor CCR10 (GPR2)4,5 and its two cognate ligands, CCL27 and CCL28 have been implicated in the regulation of epithelial immunity and related diseases. High expression of CCR10 has been noted in epithelia of skin, small intestine, colon, salivary glands, mammary glands, and fetal lung. In addition, other cell types have been reported to express high levels of CCR10, such as melanocytes, dermal fibroblasts, dermal microvascular endothelial cells and skin T cells, sub-populations of immune cells such as IgE-secreting B cells and IgA-secreting plasma cells in mucosal tissues.”3
Complex of human CCR2 with orthosteric and allosteric antagonists (PDB code: 5t1a)
In vitro Activity
BI-6901 inhibits the CCL27 dependent Ca2+ flux in CHO-K cells stably transfected with human CCR10 and aequorin with an pIC50 of 9.0. The optical antipode (BI-6902), which can be used as a negative control has a pIC50 of 5.5 in this assay. Additionally BI-6536 (the racemate of BI-6901 and BI-6902) was tested in assays with different functional readouts (Ca2+ flux, cAMP production, GTP binding and chemotaxis) and different cell backgrounds (CHO-K, HEK and Ba/F3) and gave highly consistent results (see in vitro activity table).
|
Probe / Racemate / Negative Control |
BI-6901 |
BI-6536 (Racemate of BI-6901 and BI-6902) |
BI-6902 |
|
MW [Da] |
454 |
454 |
454 |
|
FLIPR Ca2+ flux (hCCL27) pIC50a |
n.a. |
9.4 |
n.a. |
|
FLIPR Ca2+ flux (hCCL28) pIC50a |
n.a. |
8.9 |
n.a. |
|
Aequorin Ca2+ flux (hCCL27) pIC50a |
9.0 |
8.7 |
5.5 |
|
Aequorin Ca2+ flux (hCCL28) pIC50a |
n.a. |
9.0 |
n.a. |
|
cAMP (hCCL27) pIC50b |
n.a. |
7.6 |
n.a. |
|
GTP-Eu (hCCL27) pIC50c |
n.a. |
8.0 |
n.a. |
|
Chemotaxis (hCCL27) pIC50d |
n.a. |
9.0 |
n.a. |
Cell lines:
a CHO-K (Aequorin, Gαq)
b HEK
c HEK membrane prep
d Ba/F3
In vitro DMPK parameters
BI-6536 (the racemate of BI-6901 and BI-6902) shows high clearance in liver microsomes (LM): human LM >93 %QH, murine LM >91% QH, rat LM >86% QH. The compound is highly bound to human plasma proteins: hPPB 99.4% bound. BI-6901 has a medium solubility across different pH ranges: (33 µg/mL @ pH 4,38 µg/mL @ pH 7).
|
Probe name |
BI-6901 |
BI-6536 (Racemate of BI-6901 and BI-6902) |
|
Solubility @ pH 7 [µg/ml] |
38 |
34 |
|
Liver microsome clearance [% QH] human / mouse |
91 / n.a. |
>93 / >91 |
|
Plasma protein binding human [%] |
n.a. |
99.4 |
In vivo DMPK parameters
Exposures of compound in 30% cremophore dosed in Balb-C mice:
BI-6901, 100 mg/kg ip, 1 h: 7.6 ± 4.5 µM, 7 h: 0.2 ± 0.2 µM;
30 mg/kg ip, 1 h: 3.7 ± 0.4 µM, 7 h: not detected.
BI-6902, 100 mg/kg ip, 1 h: 18 ± 2 µM; 7 h: not detected;
30 mg/kg ip, 1 h: 3.2 ± 0.8 µM, 7 h: not detected;
99% plasma protein binding for both compounds
In vivo pharmacology
High clearance compound. High doses and i.p. administration needed to obtain sufficient levels.
The murine cellular potency and apparent specificity of BI-6901 qualified it as a tool to test the impact of CCR10 antagonism on dermal inflammation. BI-6901 was investigated for efficacy against 2,4-dinitrofluorobenzene (DNFB) murine contact hypersensitivity, with BI-6902 serving as a structurally related negative control.1 The model captures a predominantly T cell dependent inflammatory response of sensitized mice to topical DNFB challenge on the ear.6 Due to high clearance in mice a 100 mg/kg dose delivered intraperitoneally at 0 and 8 h was required to maintain plasma exposure near or above the murine IC50 of BI-6901 over the majority of the experiment (satellite exposures of the compounds see in vivo DMPK parameter section). Nonetheless, BI-6901 exhibited a dose-dependent anti-inflammatory response against DNFB stimulated ear swelling in sensitized mice. While the eutomer BI-6901 showed efficacy, the distomer BI-6902 demonstrated no activity, consistent with -the stereospecificity of CCR10 antagonism.1 The level of efficacy observed for BI-6901 was similar to that observed with anti-CCL27 antibody in the same model (60-85%).7
Negative control
BI-6902
BI-6902 is the optical antipode of BI-6901 and inhibits the CCL27 dependent Ca2+ flux in CHO-K cells stably transfected with human CCR10 and aequorin with an pIC50 5.5. It was used as a negative control in in vivo pharmacology experiments (see in vivo pharmacology section).
Absolute configuration (S) assigned in analogy to example #10 in Reference 1.
Selectivity
No meaningful binding or activity was observed against 29 GPCR’s, including 6 chemokine receptors (see supplementary material).1
|
Probe name |
BI-6901 |
|
Cerep® |
No |
|
Eurofins-Panlabs® |
Yes |
|
Invitrogen® |
No |
|
DiscoverX® |
No |
|
Dundee |
No |
Summary
Our compound is the first small molecule inhibitor of the Chemokine receptor CCR10.1-3 It is a potent and selective compound and suitable for in vivo validation.
Supplementary data
References
N-Arylsulfonyl-α-amino carboxamides are potent and selective inhibitors of the chemokine receptor CCR10 that show efficacy in the murine DNFB model of contact hypersensitivity
Abeywardane A., Caviness G., Choi Y., Cogan D., Gao A., Goldberg D., Heim-Riether A., Jeanfavre D., Klein E., Kowalski J. A., Mao W., Miller C., Moss N., Ramsden P., Raymond E., Skow D., Smith-Keenan L., Snow R. J., Wu F., Wu J. P., Yu Y.
Bioorg. Med. Chem. Lett. 2016, 26, 5277–5283.
U.S. Patent
Françoise Jung, Frank O. Gombert, Daniel Obrecht, Christian Bisang, Sophie Barthélémy, Alexander Lederer, Eric Chevalier
8,754,038, 2014.
Protective effect of a Protein Epitope Mimetic CCR10 antagonist, POL7085, in a model of allergic eosinophilic airway inflammation
Daubeuf F., Jung F., Douglas G. J., Chevalier E., Frossard N.
Respir Res. 2015, 16, 77.
Cutting Edge: Identification of the Orphan Receptor G-Protein-Coupled Receptor 2 as CCR10, a Specific Receptor for the Chemokine ESkine
Jarmin D. I., Rits M., Bota D., Gerard N. P., Graham G. J., Clark-Lewis I., Gerard C.
J. Immunol. 2000, 164, 3460–3464.
Cutting Edge: The Orphan Chemokine Receptor G Protein-Coupled Receptor-2 (GPR-2, CCR10) Binds the Skin-Associated Chemokine CCL27 (CTACK/ALP/ILC)
Homey B., Wang W., Soto H., Buchanan M. E., Wiesenborn A., Catron D., Müller A., McClanahan T. K., Dieu-Nosjean M. C., Orozco R., Ruzicka T., Lehmann P., Oldham E., Zlotnik A.
J. Immunol. 2000, 164, 3465–3470.
The role of CD4+ and CD8+ T cells in contact hypersensitivity and allergic contact dermatitis
Saint-Mezard P., Bérard F., Dubois B., Kaiserlian D., Nicolas J. F.
Eur. J. Dermatol. 2004, 14, 131–138.
CCL27−CCR10 interactions regulate T cell−mediated skin inflammation
Homey B., Alenius H., Müller A., Soto H., Bowman E. P., Yuan W., McEvoy L., Lauerma A. I., Assmann T., Bünemann E., Lehto M., Wolff H., Yen D., Marxhausen H., To W., Sedgwick J., Ruzicka T., Lehmann P., Zlotnik A.
Nat. Med. 2002, 8, 157–165.
