CUDC-427 (GDC-0917)

GDC-0917 is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins. It targets cellular IAP1 (cIAP1), leading to its degradation. [1]

GDC-0917 (0.1 nM-10 μM) 导致 PBMC 中 cIAP1 水平出现浓度依赖性下降，浓度高于 0.1 µM (56.5 ng/mL) 时抑制率超过 80%[1]。

---

在体外免疫测定中，GDC-0917 在外周血单个核细胞（PBMCs）中诱导了cIAP1蛋白水平的浓度依赖性降低。在浓度大于0.1 µM（56.5 ng/mL）时，观察到大于80%的cIAP1抑制。使用抑制性Imax模型表征了浓度与cIAP1降低之间的关系。[1]

GDC-0917 具有良好的耐受性，所有剂量组的平均体重下降<11%。 GDC-0917 (0.08-16.3 mg/kg) 在 MDA-MB-231-X1.1 乳腺癌异种移植物中以剂量依赖性方式表现出抗肿瘤活性。在小鼠 (12.0 mL/min/kg)、大鼠 (27.0 mL/min/kg) 和狗 (15.3 mL/min/kg) 中，GDC-0917 的清除量为低至中等，而在猴子 (67.6 mL/min/kg) 较高。猴子的口服生物利用度是所有物种中最低的[1]。

---

在携带MDA-MB-231-X1.1乳腺癌异种移植瘤的雌性SCID-beige小鼠中，GDC-0917 显示出剂量依赖性的抗肿瘤活性。每日口服给药21天导致肿瘤生长抑制，在剂量大于5.43 mg/kg时观察到轻微的肿瘤消退。该化合物耐受性良好，所有剂量组平均体重下降均小于11%。[1]

在外周血单个核细胞（PBMCs）中进行了体外cIAP1免疫测定。收集全血，混合，并与载体或GDC-0917（0.0001–10 µM）在室温避光条件下孵育约16小时。然后通过离心分离PBMCs并清洗。细胞沉淀用含有蛋白酶抑制剂的细胞裂解缓冲液裂解。裂解液离心后，使用微量二喹啉甲酸测定法测定总细胞蛋白浓度。cIAP1浓度使用免疫测定法测定，该法涉及将PBMC样品与生物素化的山羊抗人cIAP1多克隆抗体和钌标记的大鼠抗人cIAP1单克隆抗体在测定稀释剂中孵育。该混合物与用牛血清白蛋白封闭的链霉亲和素包被板孵育。洗涤后，加入与钌标记抗体反应的化学发光底物，cIAP1浓度通过基于化学发光信号的标准曲线的四参数回归分析确定。cIAP1水平表示为DMSO对照的百分比。[1]

Mouse PK Study: Female SCID-beige mice were administered single intravenous (1 mg/kg) or oral (3 mg/kg) doses of GDC-0917. For IV dosing, the compound was formulated in 15% hydroxypropyl-β-cyclodextrin and 20 mM succinic acid in water. For oral dosing, it was formulated in 0.5% w/v methylcellulose with 0.2% v/v Tween 80. Blood samples were collected at various time points via terminal cardiac puncture into EDTA tubes, centrifuged, and plasma harvested for LC-MS/MS analysis. [1]
Rat PK Study: Male Sprague-Dawley rats were administered single IV (1 mg/kg) or oral (5 mg/kg) doses of GDC-0917 using the same formulations as in mice. Blood samples were collected from the jugular vein at specified times into EDTA tubes, processed to plasma, and analyzed via LC-MS/MS. [1]
Dog PK Study: Male beagle dogs received a single IV dose (1 mg/kg) formulated in 15% hydroxypropyl-β-cyclodextrin and 20 mM succinic acid in water, or a single oral dose (1 mg/kg) formulated in 0.5% w/v methylcellulose with 0.2% v/v Tween 80. Blood samples were collected from a peripheral vein into EDTA tubes, processed to plasma, and urine was also collected. Samples were stored at -70°C until LC-MS/MS analysis. [1]
Monkey PK Study: Male cynomolgus monkeys received a single IV dose (1 mg/kg) via the saphenous vein formulated as for dogs, or a single oral dose (2 mg/kg) formulated as for dogs. Blood samples were collected from the femoral vein into EDTA tubes, processed to plasma, and urine was collected from IV-dosed animals. Samples were stored at -70°C until LC-MS/MS analysis. [1]
MDA-MB-231-X1.1 Xenograft Efficacy Study: Female SCID-beige mice were implanted subcutaneously with MDA-MB-231-X1.1 breast adenocarcinoma cells. When tumor volumes reached 100–300 mm³, mice were assigned to treatment groups. Groups received once-daily oral doses of vehicle or GDC-0917 (0.08 to 16.30 mg/kg) for 21 days. The compound was formulated in 15% hydroxypropyl-β-cyclodextrin and 20 mM succinic acid in water. Tumor volumes and body weights were measured twice weekly. [1]

GDC-0917 showed low to moderate plasma clearance in mouse (12.0 mL/min/kg), rat (27.0 mL/min/kg), and dog (15.3 mL/min/kg), and high clearance in monkey (67.6 mL/min/kg). [1]
Terminal half-life (t1/2) ranged from 0.825 hours in monkey to 6.12 hours in dog. [1]
Volume of distribution at steady state (Vss) was low to moderate across species (mouse: 1.27 L/kg, rat: 1.81 L/kg, dog: 4.09 L/kg, monkey: 4.25 L/kg). [1]
Oral bioavailability was high in mouse (93.5%), rat (77.0%), and dog (97.0%), but low in monkey (16.8%). [1]
Renal clearance was negligible in dog (0.0897 mL/min/kg, PO group) and monkey (1.44 mL/min/kg, IV group), accounting for <1% and ~2% of plasma clearance, respectively. [1]
Predicted human hepatic clearance based on in vitro-in vivo extrapolation from hepatocyte studies was 11.5 mL/min/kg. [1]
Predicted human volume of distribution using simple allometry was 6.69 L/kg. [1]
Predicted human half-life based on predicted clearance and volume was 6.70 hours. [1]
In human cancer patients, after a single 5 mg oral dose, the observed mean Cmax was 4.57 ng/mL, tmax ranged from 2–6 hours, AUCtot was 37.1 ng·h/mL, and t1/2 was 3.98 hours. [1]

GDC-0917 was well tolerated in the MDA-MB-231-X1.1 xenograft study, with all dose groups experiencing less than 11% decrease in mean body weight. [1]

[1]. Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist. Drug Metab Dispos. 2013 Dec;41(12):2104-13.

CUDC-427 has been used in trials studying the treatment of LYMPHOMA and Solid Cancers.
Smac Mimetic GDC-0917 is an orally available, monovalent mimetic of second mitochondrial-derived activator of caspases (Smac/DIABLO) and inhibitor of IAPs (Inhibitor of Apoptosis Proteins) with potential antineoplastic activity. Smac mimetic GDC-0917 binds to the Smac binding groove on IAPs, including the direct caspase inhibitor X chromosome-linked IAP (XIAP) and the cellular IAPs 1 and 2. This inhibits the activities of these IAPs and promotes the induction of apoptosis through apoptotic signaling pathways. IAPs are overexpressed by many cancer cell types and suppress apoptosis by binding to and inhibiting active caspases-3, -7 and -9 via their baculoviral lAP repeat (BIR) domains.

---

GDC-0917 is an orally available second-generation IAP antagonist developed for the treatment of various cancers. [1]
It induces degradation of cIAP1, a member of the IAP protein family involved in regulating apoptosis and suppressing caspase activity. [1]
Modeling and simulation techniques were used extensively to predict human pharmacokinetics, pharmacodynamics (ED50 and ED90 doses), and clinical trial feasibility based on preclinical data. [1]
The predicted human ED50 and ED90 doses for tumor growth inhibition were 72 mg and 660 mg, respectively, based on translational PK-PD analysis of xenograft data. [1]
Simulations of the 5 mg starting dose in humans predicted PK profiles and cIAP1 modulation that agreed well with early clinical observations. [1]

C29H36N6O4S

564.698945045471

564.252

C, 61.68; H, 6.43; N, 14.88; O, 11.33; S, 5.68

1446182-94-0

1446182-94-0

71600094

white solid powder

4.86

157.7

3

8

9

40

883

3

O=C([C@H](CCC1)N1C([C@H](C2CCCCC2)NC([C@H](C)NC)=O)=O)NC3=C(C4=CC=CC=C4)N=C(C5=NC=CO5)S3

HSHPBORBOJIXSQ-HARLFGEKSA-N

InChI=1S/C29H36N6O4S/c1-18(30-2)24(36)32-23(20-12-7-4-8-13-20)29(38)35-16-9-14-21(35)25(37)34-27-22(19-10-5-3-6-11-19)33-28(40-27)26-31-15-17-39-26/h3,5-6,10-11,15,17-18,20-21,23,30H,4,7-9,12-14,16H2,1-2H3,(H,32,36)(H,34,37)/t18-,21-,23-/m0/s1

(2S)-1-[(2S)-2-cyclohexyl-2-[[(2S)-2-(methylamino)propanoyl]amino]acetyl]-N-[2-(1,3-oxazol-2-yl)-4-phenyl-1,3-thiazol-5-yl]pyrrolidine-2-carboxamide

CUDC427; CUDC-427; CUDC 427; GDC0917; GDC-0917; GDC 0917

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)

DMSO: ~50 mg/mL (~88.54 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.43 mM) (饱和度未知) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 25.0 mg/mL澄清DMSO储备液加入到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。

---

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。