Smo ( IC50 = 4 nM )

体外活性：在体外微粒体测定中，PF-04449913 在大鼠中具有高清除率，在狗和人类中具有低清除率，且不抑制任何主要细胞色素 P450 亚型。激酶测定：Glasdegib（以前称为 PF-04449913）是一种新型强效、口服生物可利用的 Hedgehog (Hh) 信号通路中 Smoothened (Smo) 小分子抑制剂，IC50 为 5 nM。 Hh信号通路在细胞生长、分化和修复中发挥着重要作用。在各种类型的癌症中都观察到了 Hh 通路信号的组成型激活。在 Ptch1+/-p53+/- 同种异体移植模型中，Glasdegib 在降低小鼠 Shh 靶基因表达的剂量下显着减少髓母细胞瘤的生长。在基质共培养实验中，FACS 分析表明，与正常祖细胞相比，PF-04449913 的 BC LSC 显着减少。细胞检测：在 Hedgehog (Hh) 信号通路中，Hh 配体与其受体 Patched 的结合导致 smoothened 的激活，并随后激活三个转录因子 Gli1、Gli2 和 Gli3。然后它导致细胞增殖。作为 smoothened 的拮抗剂，PF-04449913 被开发用于治疗癌症。

在大鼠和狗中，PF-04449913 显示出高清除率和良好的口服生物利用度

Glasdegib 是一种新型强效小分子抑制剂，IC50 为 5 nM，是 Hedgehog (Hh) 信号通路中 Smoothened (Smo) 的口服生物利用抑制剂。它以前被称为 PF-04449913。在细胞中，Hh 信号通路对于生长、分化和修复至关重要。在许多不同类型的癌症中，Hh 通路信号传导的组成型激活已被报道。在 Ptch1+/-p53+/- 的同种异体移植模型中，Glasdegib 显着抑制髓母细胞瘤的生长，其剂量也可减少小鼠 Shh 靶基因的表达。与正常祖细胞相比，FACS 分析显示，在基质共培养实验中，PF-04449913 使 BC LSC 显着减少。

BMS-354825 (50 nM)、Glasdegib (PF-04449913) (1 μM) 或这些治疗的组合用于治疗 BC CML 中的 CD34⁺细胞或正常细胞。将 M2-10B4 (M2) 和 SL/SL (SL) 小鼠骨髓基质细胞系以 1:1 混合物以终浓度 100,000 个细胞/mL 铺板一天，然后与 10,000–20,000 个 CD34 共培养 ⁺BC CML 或正常祖细胞。第 14 天时，培养一周后，对祖细胞进行评分并进行 FACS 分类以进行造血祖细胞测定。使用以下方法评估正常人造血干细胞和祖细胞的存活率：将经过辐射的（20 格雷）OP9（M2 克隆）基质细胞与 50,000 个人 CD34⁺ 脐带血细胞、载体、或 Glasdegib (PF-04449913) 在 AlphaMEM 中，含有 20% Hyclone FBS、1% 笔链球菌谷氨酰胺，并补充有 50 ng/mL SCF、10 ng/mL 血小板生成素和 10 ng/mL Flt3。使用每周 FACS 分析记录结果[1]。

Absorption, Distribution and Excretion
Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml. The oral bioavailability of glasdegib is reported to be of 55%. In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml. The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal.
From a single oral dose of 100 mg radiolabeled glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form.
Glasdegib reported volume of distribution in a dose of 50 mg is 225 L. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies.
The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h. The geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies.

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Metabolism / Metabolites
After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose.

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Biological Half-Life
The reported half-life of glasdegib is of 17.4 hours.

Hepatotoxicity
Elevations in serum ALT levels are common during glasdegib therapy, occurring in 31% of patients and rising above 5 times the upper limit of the normal range in 11%. Glasdegib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with the use of hedgehog inhibitors, their potential for causing liver injury is not well defined.
Likelihood score: E* (unproved but suspected cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on glasdegib during breastfeeding. It is 91% bound to plasma proteins, so amounts in milk are likely to be low. With a half-life of 17.4 hours, it is likely to be eliminated from milk by 4 to 7 days after the last dose. However, the manufacturer recommends that breastfeeding be discontinued during glasdegib therapy and for at least 30 days after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile.

[1]. GLI2 inhibition abrogates human leukemia stem cell dormancy. J Transl Med. 2015 Mar 21;13:98.

Pharmacodynamics
In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in cell population expressing leukemic stem cell markers. In clinical trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in skin. In this same study 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double to what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib.

C21H22N6O

374.44

374.185

C, 67.36; H, 5.92; N, 22.44; O, 4.27

1095173-27-5

1095173-27-5; 2030410-25-2; 1095173-64-0 (HCl); 1352568-48-9 (2HCl)

25166913

White solid powder

1.3±0.1 g/cm3

633.4±55.0 °C at 760 mmHg

336.9±31.5 °C

0.0±1.9 mmHg at 25°C

1.686

2.77

100.33

3

4

3

28

595

2

O=C(NC1=CC=C(C#N)C=C1)N[C@H]2C[C@H](C3=NC4=CC=CC=C4N3)N(C)CC2

SFNSLLSYNZWZQG-VQIMIIECSA-N

InChI=1S/C21H22N6O/c1-27-11-10-16(24-21(28)23-15-8-6-14(13-22)7-9-15)12-19(27)20-25-17-4-2-3-5-18(17)26-20/h2-9,16,19H,10-12H2,1H3,(H,25,26)(H2,23,24,28)/t16-,19-/m1/s1

1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.08 mg/mL (5.55 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (5.55 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (5.55 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。