Remibrutinib

Catalog No.S9660 Batch:S966001

Technical Data

Formula	C₂₇H₂₇F₂N₅O₃
Molecular Weight	507.53	CAS No.	1787294-07-8
Solubility (25°C)*	In vitro	DMSO	100 mg/mL (197.03 mM)
		Ethanol	4 mg/mL (7.88 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description

Remibrutinib is a potent, highly selective covalent inhibitor of bruton tyrosine kinase (BTK) with IC50 of 1.3 nM, 2.5 nM and 18 nM for BTK, FcγR-induced IL8 and anti-IgM/IL4-induced CD69, respectively. Remibrutinib (LOU064) exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for the treatment of autoimmune diseases.

Targets

BTK ^[1] (Cell-free assay)	IL-8 ^[1] (Cell-free assay)	CD69 ^[1] (Cell-free assay)
1.3 nM	2.5 nM	18 nM

In vitro

LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases.^[1]

In vivo

LOU064 demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis.^[1]

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines human monocytic cell line THP1, Human Blood B cell and Basophil. Concentrations 3 nM, 10 nM, 30 nM, 100 nM, 300 nM Incubation Time 25 min, 50 min, 75 min, 100 min Method The effects of LOU064 on signaling from the activating FcγR are assessed in the human monocytic cell line THP1 (ATCC, TIB-202). The THP1 cell line expresses the two activating FcγRs CD32a (FcγRII2) and CD64 (FcγRI) that signal through BTK. Briefly, 384 well culture plates are coated with pooled non-specific human IgG fraction. Serial compound dilutions are dispensed into the IgG-coated plates containing a small volume of tissue culture medium. Then THP1 cells that are pre-differentiated by vitamin D3 treatment for 5 days are added to each well. Twenty-four hours later the secretion of IL-8 in the supernatant of these culture wells is assessed by a homogenous immunoassay.
Animal Study:^{^[1]}	Animal Models Female Lewis rats, female C57BL/6 mice, male beagle dog. Dosages 1 mg/kg, 3 mg/kg Administration IV, Oral gavage

Cell Assay:^{^[1]}

Cell lines
human monocytic cell line THP1, Human Blood B cell and Basophil.
Concentrations
3 nM, 10 nM, 30 nM, 100 nM, 300 nM
Incubation Time
25 min, 50 min, 75 min, 100 min
Method
The effects of LOU064 on signaling from the activating FcγR are assessed in the human monocytic cell line THP1 (ATCC, TIB-202). The THP1 cell line expresses the two activating FcγRs CD32a (FcγRII2) and CD64 (FcγRI) that signal through BTK. Briefly, 384 well culture plates are coated with pooled non-specific human IgG fraction. Serial compound dilutions are dispensed into the IgG-coated plates containing a small volume of tissue culture medium. Then THP1 cells that are pre-differentiated by vitamin D3 treatment for 5 days are added to each well. Twenty-four hours later the secretion of IL-8 in the supernatant of these culture wells is assessed by a homogenous immunoassay.

Animal Study:^{^[1]}

Animal Models
Female Lewis rats, female C57BL/6 mice, male beagle dog.
Dosages
1 mg/kg, 3 mg/kg
Administration
IV, Oral gavage

References

[1] Daniela Angst, et al. J Med Chem. 2020 May 28;63(10):5102-5118.

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SHIPPING AND STORAGE
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