4LGU

Crystal structure of clAP1 BIR3 bound to T3226692

Summary for 4LGU

• Entry DOI: 10.2210/pdb4lgu/pdb
• Related: 4LGE
• Related PRD ID: PRD_001141
• Descriptor: Baculoviral IAP repeat-containing protein 2, ZINC ION, (3S,8aR)-N-((R)-chroman-4-yl)-2-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)octahydropyrrolo[1,2-a]pyrazine-3-carboxamide, ... (4 entities in total)
• Functional Keywords: lap family, 3 bir repeats, card domain, 1 ring-type zinc finger, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q13490
• Total number of polymer chains: 2
• Total formula weight: 27771.84

Authors

Dougan, D.R.,Mol, C.D.,Snell, G.P. (deposition date: 2013-06-28, release date: 2013-08-28, Last modification date: 2024-05-22)

Primary citation

Asano, M.,Hashimoto, K.,Saito, B.,Shiokawa, Z.,Sumi, H.,Yabuki, M.,Yoshimatsu, M.,Aoyama, K.,Hamada, T.,Morishita, N.,Dougan, D.R.,Mol, C.D.,Yoshida, S.,Ishikawa, T.
Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists.
Bioorg.Med.Chem., 21:5725-5737, 2013

PubMed Abstract: We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b', which were obtained by Simmons-Smith cyclopropanation of ethylester 3a and silyl ether 3b'. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner.

PubMed: 23928071
DOI: 10.1016/j.bmc.2013.07.020

Experimental method

X-RAY DIFFRACTION (2 Å)