4MU7

Crystal structure of cIAP1 BIR3 bound to T3450325

Summary for 4MU7

• Entry DOI: 10.2210/pdb4mu7/pdb
• Related: 4MTI
• Descriptor: Baculoviral IAP repeat-containing protein 2, ZINC ION, (3S,10aS)-2-[(2S)-2-cyclohexyl-2-{[(2S)-2-(methylamino)butanoyl]amino}acetyl]-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole-3-carboxamide, ... (4 entities in total)
• Functional Keywords: ring-type zinc finger, ligase, apoptosis inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q13490
• Total number of polymer chains: 2
• Total formula weight: 27895.98

Authors

Snell, G.P.,Dougan, D.R. (deposition date: 2013-09-20, release date: 2013-12-11, Last modification date: 2024-02-28)

Primary citation

Shiokawa, Z.,Hashimoto, K.,Saito, B.,Oguro, Y.,Sumi, H.,Yabuki, M.,Yoshimatsu, M.,Kosugi, Y.,Debori, Y.,Morishita, N.,Dougan, D.R.,Snell, G.P.,Yoshida, S.,Ishikawa, T.
Design, synthesis, and biological activities of novel hexahydropyrazino[1,2-a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells.
Bioorg.Med.Chem., 21:7938-7954, 2013

PubMed Abstract: We previously reported octahydropyrrolo[1,2-a]pyrazine derivative 2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound 2 was susceptible to MDR1 mediated efflux, we developed another scaffold, hexahydropyrazino[1,2-a]indole, using structure-based drug design. The fused benzene ring of this scaffold was aimed at increasing the lipophilicity and decreasing the basicity of the scaffold to improve the membrane permeability across MDR1 expressing cells. We established a chiral pool synthetic route to yield the desired tricyclic chiral isomers. Chemical modification of the core scaffold led to a representative compound 50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC50 23 nM and cellular IAP [cIAP]: IC50 1.1 nM) and cell growth inhibition (MDA-MB-231 cells: GI50 2.8 nM) with high permeability and low potential of MDR1 substrate.

PubMed: 24169315
DOI: 10.1016/j.bmc.2013.09.067

Experimental method

X-RAY DIFFRACTION (1.79 Å)