Screening multicomponent reactions for X-linked inhibitor of apoptosis-baculoviral inhibitor of apoptosis protein repeats domain binder.
We report a second example of a general reaction screening approach to discover low molecular weight inhibitors of protein protein interactions. On the basis of the known pharmacophore model of SMAC mimetics, we predicted several inhibitors based on four different multicomponent reactions. The predicted inhibitors were subsequently synthesized, tested, and found to bind to the antiapoptotic protein X-linked inhibitor of apoptosis protein (XIAP) and showed cellular activity. Also the compounds are currently not highly potent. They could form a starting point for future medicinal chemistry optimization.
University of Pittsburgh, Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.
Ilaria
I
Monfardini
Jui-Wen
JW
Huang
Barbara
B
Beck
Jason F
JF
Cellitti
Maurizio
M
Pellecchia
Alexander
A
Dömling
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D057786:Peptidomimetics; D010879:Piperazines; D013777:Tetrazoles; D013844:Thiazoles; D053778:Thiazolidines; D051636:X-Linked Inhibitor of Apoptosis Protein