CGI-1746

SKU: orb1223679

Description

CGI-1746 is a potent, highly selective, second-generation BTK inhibitor with IC50 of 1.9 nM, displays 1,000-fold selectivity over Tec and Src family kinases; displays no significant binding affinity for other 385 kinases; abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production in macrophages, blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis; inhibits myeloma-like tumors both in vitro and in vivo.

Images & Validation

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Key Properties

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CAS Number	910232-84-7
MW	579.6887
Purity	>98% (HPLC)
Formula	C₃₄H₃₇N₅O₄
SMILES	O=C(NC1=CC=CC(C(N=C2NC3=CC=C(C(N4CCOCC4)=O)C=C3)=CN(C)C2=O)=C1C)C5=CC=C(C(C)(C)C)C=C5
Target	BTK
Solubility	10 mM in DMSO

Bioactivity

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In Vivo

CGI1746 abrogates B cell-dependent arthritis. CGI1746 treatment (100 mg/kg, s. c, twice-daily dosing) results in significant inhibition (97%) of overall clinical arthritis scores. CGI1746 treatment substantially reduces TNFα, IL-1β and IL-6, as well as MCP1 and MIP-1α on both the mRNA and protein level in the passive anti-collagen II antibody-induced arthritis (CAIA) model. CGI1746 shows comparable efficacy to TNFα blockade and significantly reduces clinical scores, as well as joint inflammation, in mice or rats with established arthritis.

In Vitro

CGI1746 is specific for Btk, with appr 1, 000-fold selectivity over Tec and Src family kinases. In an ATP-free competition binding assay, the dissociation constant for Btk is 1.5 nM. CGI1746 inhibits Btk activity in a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 inhibits both auto- and transphosphorylation steps necessary for enzyme activation. CGI1746 completely inhibits anti-IgM-induced murine and human B cell proliferation, with IC50s of 134 nM and 42 nM, respectively, but has no effect on anti-CD3- and anti-CD28-induced T cell proliferation. CGI1746 potently inhibits the proliferation of CD27+IgG+ B cells isolated from the tonsils of four human donors with an average IC50 of 112 nM. In macrophages, CGI1746 abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. CGI1746 potently inhibits TNFα, IL-1β and, to a lesser extent, IL-6 (three- to eight-fold higher IC50) production in human monocytes stimulated with immobilized or soluble immune complexes. CGI-1746 does not kill cells as well as the irreversible BTK inhibitors at the same drug concentration. CGI-1746 significantly reduces phosphorylation of both the BTK-A and BTK-C proteins, indicating the auto-phosphorylation of the BTK-C isoform is inhibited in a manner similar to BTK-A. CGI-1746 does not kill LNCaP or DU145 prostate cancer cells at the same concentrations as Ibrutinib or AVL-292, but it demonstrates similar inhibition of BTK phosphorylation at tyrosine 233 in the SH3 domain.

Storage & Handling

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Storage	Storage temperature: -20°C. Stability: ≥ 2 years
Expiration Date	12 months from date of receipt.
Disclaimer	For research use only

Alternative Names

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CGI1746 | CGI 1746

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Gene Symbol

BTK

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CGI-1746 (orb1223679)

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Purity:	98.27%
CAS Number:	910232-84-7
MW:	579.69
Formula:	C₃₄H₃₇N₅O₄

CGI-1746

Description

Images & Validation

Key Properties

Bioactivity

Storage & Handling

Alternative Names

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CGI-1746 (orb1223679)

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