| 名稱 | Sotuletinib |
| 描述 | Sotuletinib (BLZ945) is an orally active, effective and specific CSF-1R inhibitor (IC50: 1 nM), >1000-fold selective against its closest receptor tyrosine kinase homologs. |
| 細胞實驗 | Cell growth rate is determined using the MTT cell proliferation kit. Briefly, cells are plated in triplicate in 96-well plates: 1,000 cells per well for glioma cell lines, 5 x 1,000 cells per well for BMDM and CRL-2467, and 2.5 x 1,000 cells per well for HUVEC and HBMEC cell lines. For all experiments, media is changed every 48 h. Cells are grown in the presence or absence of 6.7–6,700 nM of BLZ945, or 8 μg/mL of CSF-1R neutralizing antibody. BMDM and CRL-2467 cells were supplemented with 10 ng/mL and 30 ng/ mL recombinant mouse CSF-1, respectively. Reduction of the MTT substrate is detected by colorimetric analysis using a plate reader as per the manufacturer's protocol, and measured at 595 nm and 750 nm on a spectraMax 340pc plate reader.(Only for Reference) |
| 激酶實驗 | Inhibition of biochemical TrkA, TrkB and TrkC: TrkA and TrkC biochemical assays are carried out by HTRF method. The reaction mixtures contains 1 μM peptide substrate, 1 μM ATP, and either 1.8 nM TrkA or 34 nM TrkC in the reaction buffer (50 mM HEPES pH 7.1, 10 mM MgCl2, 2 mM MnCl2, 0.01% BSA, 2.5 mM DTT and 0.1 mM Na3VO4) at a final volume of 10 μL. All reactions are carried out at room temperature in white ProxiPlate? 384-well Plus plates and are quenched with 5 μL of 0.2 mM EDTA at 60 min. Five μL of the detection reagents (2.5 ng PT66K and 0.05 μg SAXL per well) are added, the plates are incubated at room temperature for 1 h and then read in EnVision reader. Compounds are diluted into assay mixture (final DMSO 0.5%), and IC50 values are determined by 12-point (from 50 to 0.000282 μΜ) inhibition curves in duplicate under the assay conditions. TrkB biochemical assay is carried out by caliper microfluidic method. The reaction mixtures contained 1 μM peptide substrate, 10 μM ATP, and 2 nM TrkB in a reaction buffer containing 100 mM HEPES, pH 7.5, 5 mM MgCl2, 0.01% Triton X-100, 0.1% BSA, 1 mM DTT, 10 μΜNa3VO4, and 10 μΜBeta-Glycerophosphate. The reactions are carried out at room temperature for 3 hrs, and the products are determined by Caliper EZ-reader. Compounds are diluted into assay mixture (final DMSO 1%), and IC50 values are determined by 12-point (from 50 to 0.000282 μΜ) inhibition curves in duplicate under the assay conditions. |
| 體外活性 | 在骨髓衍生的巨噬細胞（BMDMs）中，Sotuletinib 特異性抑制 CSF-1 依賴的增殖，其 EC50 為 67 nM，并降低 CSF-1R 的磷酸化。Sotuletinib 阻斷了巨噬細胞與膠質(zhì)瘤細胞之間對彼此的生存、增殖和/或極化產(chǎn)生的相互作用，從而促進腫瘤發(fā)生。[1] |
| 體內(nèi)活性 | 在攜帶膠質(zhì)瘤的小鼠身上，Sotuletinib 通過抑制 CSF-1R 阻斷腫瘤進展并顯著提高存活率。Sotuletinib 還能夠抑制體內(nèi)患者衍生的傾向神經(jīng)型腫瘤球和細胞系的原位腫瘤生長。[1] Sotuletinib (200 mg/kg, 經(jīng)口) 有效減緩了小鼠乳腺腫瘤病毒驅(qū)動的多瘤病毒中間T抗原(MMTV-PyMT)乳腺癌發(fā)生模型和表達角蛋白14的人乳頭狀瘤病毒16型(K14-HPV-16)轉(zhuǎn)基因?qū)m頸癌模型中惡性細胞的生長。[2] |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 18.33 mg/mL (46.01 mM), Sonication is recommended.
Ethanol : 3 mg/mL (7.52 mM), Heating is recommended.
H2O : < 1 mg/mL (insoluble or slightly soluble)
|
| 關(guān)鍵字 | CSF1R | CSF-1R | CSF-1 receptor | inhibit | c-Fms | Inhibitor | colony stimulating factor 1 receptor | BLZ-945 | Sotuletinib | BLZ 945 |
| 相關(guān)產(chǎn)品 | AZD7507 | Cerdulatinib hydrochloride | PLX647 | Masitinib | GW2580 | c-Fms-IN-1 | Tandutinib | c-Fms-IN-13 | Pexidartinib | PLX5622 | c-Fms-IN-3 | Pazopanib Hydrochloride |
| 相關(guān)庫 | 抑制劑庫 | 抗癌活性化合物庫 | 經(jīng)典已知活性庫 | 已知活性化合物庫 | 激酶抑制劑庫 | 膜蛋白靶向化合物庫 | 酪氨酸激酶分子庫 | 藥物功能重定位化合物庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |