3UW4: Crystal Structure Of Ciap1 Bir3 Bound To Gdc0152

Citation:
Abstract
A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 +/- 3 mL/min/kg, and the volume of distribution was 0.6 +/- 0.2 L/kg.
PDB ID: 3UW4Download
MMDB ID: 97450
PDB Deposition Date: 2011/11/30
Updated in MMDB: 2017/08
Experimental Method:
x-ray diffraction
Resolution: 1.79  Å
Source Organism:
Similar Structures:
Biological Unit for 3UW4: dimeric; determined by author and by software (PISA)
Molecular Components in 3UW4
Label Count Molecule
Protein (1 molecule)
1
Baculoviral IAP Repeat-containing Protein 2, Baculoviral IAP Repeat-containing Protein 4
Molecule annotation
Nucleotide(1 molecule)
1
Gdc0152
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

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