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.

Physicochemical Properties

Molecular Formula	C29H36N6O4S
Molecular Weight	564.698945045471
Exact Mass	564.252
Elemental Analysis	C, 61.68; H, 6.43; N, 14.88; O, 11.33; S, 5.68
CAS #	1446182-94-0
Related CAS #	1446182-94-0
PubChem CID	71600094
Appearance	white solid powder
LogP	4.86
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	9
Heavy Atom Count	40
Complexity	883
Defined Atom Stereocenter Count	3
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
InChi Key	HSHPBORBOJIXSQ-HARLFGEKSA-N
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
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
Synonyms	CUDC427; CUDC-427; CUDC 427; GDC0917; GDC-0917; GDC 0917
HS Tariff Code	2934.99.9001
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)

Biological Activity

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].
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].
References	[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.
Additional Infomation	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.

Solubility Data

Solubility (In Vitro)

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

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.