| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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Purity: ≥98%
CUDC-427 (also known as GDC-0917) is a novel, potent, orally available, second-generation antagonist of inhibitor of apoptosis (IAP) proteins that is being developed for the treatment of various cancers. In the mouse (12.0 ml/min/kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), GDC-0917 is cleared in a low to moderate amount, whereas the clearance in the monkey (67.6 ml/min/kg) is high. As a result, when compared to other species, monkeys had the lowest oral bioavailability. In vitro-in vivo extrapolation was used to forecast a moderate clearance (11.5 ml/min/kg) in people based on our experience with a prototype molecule with a comparable structure. Simple allometry was used to calculate a 6.69 l/kg estimate for the predicted human volume of distribution.
| Targets |
GDC-0917 is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins. It targets cellular IAP1 (cIAP1), leading to its degradation. [1]
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| ln Vitro |
GDC-0917 (0.1 nM-10 μM) icauses a concentration-dependent decrease in cIAP1 levels in PBMCs, with greater than 80% inhibition at concentrations higher than 0.1 µM (56.5 ng/mL)[1].
GDC-0917 induced concentration-dependent reduction of cIAP1 protein levels in peripheral blood mononuclear cells (PBMCs) in an in vitro immunoassay. Greater than 80% inhibition of cIAP1 was observed at concentrations greater than 0.1 µM (56.5 ng/mL). The relationship between concentration and cIAP1 decrease was characterized using an inhibitory Imax model. [1] |
| ln Vivo |
GDC-0917 is well tolerated, with all dose groups experiencing a <11% decrease in mean body weight. GDC-0917 (0.08-16.3 mg/kg) exhibits antitumor activity in a dose dependent manner in the MDA-MB-231-X1.1 Breast Cancer Xenograft. In the mouse (12.0 mL/min/kg), rat (27.0 mL/min/kg), and dog (15.3 mL/min/kg), GDC-0917 is cleared in a low to moderate amount, whereas the clearance in the monkey (67.6 mL/min/kg) is high. Monkeys have the lowest oral bioavailability of any species[1].
GDC-0917 showed dose-dependent antitumor activity in female SCID-beige mice bearing MDA-MB-231-X1.1 breast cancer xenografts. Daily oral administration for 21 days resulted in tumor growth inhibition, with slight tumor regression observed at doses >5.43 mg/kg. The compound was well tolerated with less than 11% mean body weight decrease across all dose groups. [1] |
| Cell Assay |
An in vitro cIAP1 immunoassay was performed in peripheral blood mononuclear cells (PBMCs). Whole blood was collected, pooled, and incubated with vehicle or GDC-0917 (0.0001–10 µM) for approximately 16 hours in the dark at room temperature. PBMCs were then isolated via centrifugation and washed. Cell pellets were lysed in cell extraction buffer containing protease inhibitors. Lysates were centrifuged, and total cellular protein concentration was determined using a microbicinchoninic acid assay. cIAP1 concentration was determined using an immunoassay involving incubation of the PBMC sample with a biotinylated goat anti-human cIAP1 polyclonal antibody and a ruthenium-labeled rat anti-human cIAP1 monoclonal antibody in assay diluent. This mixture was incubated with a streptavidin-coated plate blocked with bovine serum albumin. After washing, a chemiluminescent substrate reactive with the ruthenium-labeled antibody was added, and cIAP1 concentration was determined via a four-parameter regression analysis of a standard curve based on chemiluminescence signal. cIAP1 levels are expressed as a percentage of the DMSO control. [1]
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| Animal Protocol |
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] |
| ADME/Pharmacokinetics |
GDC-0917 showed low to moderate plasma clearance in mice (12.0 mL/min/kg), rats (27.0 mL/min/kg), and dogs (15.3 mL/min/kg), but high clearance in monkeys (67.6 mL/min/kg). [1]
The terminal half-life (t1/2) was 0.825 h in monkeys and 6.12 h in dogs. [1] The steady-state volume of distribution (Vss) was low to moderate in all species (mice: 1.27 L/kg, rats: 1.81 L/kg, dogs: 4.09 L/kg, monkeys: 4.25 L/kg). [1] Oral bioavailability was high in mice (93.5%), rats (77.0%), and dogs (97.0%), but low in monkeys (16.8%). [1] In dogs (0.0897 mL/min/kg, oral administration) and monkeys (1.44 mL/min/kg, intravenous administration), renal clearance was negligible, accounting for <1% and ~2% of plasma clearance, respectively. [1] Based on in vitro-in vivo extrapolation from hepatocyte studies, the predicted human liver clearance was 11.5 mL/min/kg. [1] The predicted human volume of distribution using simple allometric growth assay was 6.69 L/kg. [1] Based on the predicted clearance and volume of distribution, the predicted human half-life was 6.70 hours. [1] In human cancer patients, after a single oral administration of 5 mg, the observed mean Cmax was 4.57 ng/mL, tmax ranged from 2 to 6 hours, AUCtot was 37.1 ng·h/mL, and t1/2 was 3.98 hours. [1] |
| Toxicity/Toxicokinetics |
In the MDA-MB-231-X1.1 xenograft study, GDC-0917 was well tolerated, with mean weight loss of less than 11% in all dose groups. [1]
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| References | |
| Additional Infomation |
CUDC-427 has been used in investigational clinical trials for the treatment of lymphoma and solid tumors. GDC-0917, a Smac mimic, is an orally administered monovalent Smac mimic that mimics mitochondrial-derived caspase second activator (Smac/DIABLO) and inhibitor of apoptosis protein (IAP) inhibitors, possessing potential antitumor activity. GDC-0917 binds to the Smac binding groove on IAPs, including the direct caspase inhibitor X-linked IAP (XIAP) and cellular IAP 1 and IAP 2. This inhibits the activity of these IAPs and promotes the induction of apoptosis through apoptosis signaling pathways. IAPs are overexpressed in various cancer cell types and inhibit apoptosis by binding to and inhibiting the activity of active caspases -3, -7, and -9 through their baculoviral lAP repeat (BIR) domains. GDC-0917 is an orally administered second-generation IAP antagonist for the treatment of various cancers. [1]
It can induce the degradation of cIAP1, a member of the IAP protein family, which is involved in regulating apoptosis and inhibiting caspase activity. [1] Based on preclinical data, modeling and simulation techniques were widely used to predict the human pharmacokinetics, pharmacodynamics (ED50 and ED90 doses), and feasibility of clinical trials of GDC-0917. [1] Based on the transformational pharmacokinetic-pharmacodynamic analysis of xenograft data, the predicted human ED50 and ED90 doses for inhibiting tumor growth were 72 mg and 660 mg, respectively. [1] Human simulation results showed that the pharmacokinetic characteristics and cIAP1 regulation at the starting dose of 5 mg were in good agreement with the early clinical observation results. [1] |
| Molecular Formula |
C29H36N6O4S
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|---|---|
| Molecular Weight |
564.698945045471
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| Exact Mass |
564.252
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| Elemental Analysis |
C, 61.68; H, 6.43; N, 14.88; O, 11.33; S, 5.68
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| CAS # |
1446182-94-0
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| Related CAS # |
1446182-94-0
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| PubChem CID |
71600094
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| Appearance |
white solid powder
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| LogP |
4.86
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
40
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| Complexity |
883
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| Defined Atom Stereocenter Count |
3
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| SMILES |
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
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| InChi Key |
HSHPBORBOJIXSQ-HARLFGEKSA-N
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| InChi Code |
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
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| Chemical Name |
(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
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| Synonyms |
CUDC427; CUDC-427; CUDC 427; GDC0917; GDC-0917; GDC 0917
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~50 mg/mL (~88.54 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.43 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7709 mL | 8.8543 mL | 17.7085 mL | |
| 5 mM | 0.3542 mL | 1.7709 mL | 3.5417 mL | |
| 10 mM | 0.1771 mL | 0.8854 mL | 1.7709 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01226277 | Completed | Drug: GDC-0917 | Solid Cancers | Genentech, Inc. | October 2010 | Phase 1 |
| NCT01908413 | Terminated | Drug: CUDC-427 | Lymphoma | Curis, Inc. | July 2013 | Phase 1 |
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