CGI-1746 是一种有效的，高选择性的 Btk 抑制剂，

CGI-1746 is a potent and highly selective inhibitor of the Btk with IC₅₀ of 1.9 nM.

IC50: 1.9 nM (Btk)

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^[1]. 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 BTKphosphorylation at tyrosine 233 in the SH3 domain^[2].

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^[1].

579.69

固体

C₃₄H₃₇N₅O₄

910232-84-7

Room temperature in continental US; may vary elsewhere.

DMSO : ≥ 50 mg/mL (86.25 mM)

* "≥" means soluble, but saturation unknown.

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 2 years; -20℃, 1 year。-80℃ 储存时，请在 2 年内使用， -20℃ 储存时，请在 1 年 内使用。

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

• 1.

  请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% saline

  Solubility: ≥ 2.5 mg/mL (4.31 mM); Clear solution

   

  此方案可获得 ≥ 2.5 mg/mL (4.31 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。

• 2.

  请依序添加每种溶剂： 10% DMSO    90% (20% SBE-β-CD in saline)

  Solubility: 2.5 mg/mL (4.31 mM); Suspended solution; Need ultrasonic

   

  此方案可获得 2.5 mg/mL (4.31 mM) 的均匀悬浊液，悬浊液可用于口服和腹腔注射。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。

• 3.

  请依序添加每种溶剂： 10% DMSO    90% corn oil

  Solubility: ≥ 2.5 mg/mL (4.31 mM); Suspended solution

   

  此方案可获得 ≥ 2.5 mg/mL (4.31 mM，饱和度未知) 的均匀悬浊液，悬浊液可用于口服和腹腔注射。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

• [1]. Di Paolo, Julie A. et al. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nature Chemical Biology (2011), 7(1), 41-50  [Content Brief]

  [2]. Kokabee L, et al. Bruton's tyrosine kinase is a potential therapeutic target in prostate cancer. Cancer Biol Ther. 2015;16(11):1604-15  [Content Brief]