title: The discovery of macrocyclic XIAP antagonists from a DNA-programmed chemistry library, and their optimization to give lead compounds with in vivo antitumor activity.
abstract: Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.
authors.affiliation: †Ensemble Therapeutics Corp, 99 Erie Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Seigal
authors.affiliation: †Ensemble Therapeutics Corp, 99 Erie Street, Cambridge, Massachusetts 02139, United States.
authors.forename: William H
authors.initials: WH
authors.lastname: Connors
authors.affiliation: †Ensemble Therapeutics Corp, 99 Erie Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Fraley
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Emanuel
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Kyoung
authors.initials: K
authors.lastname: Kim
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Naglich
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Pokross
authors.forename: Shana L
authors.initials: SL
authors.lastname: Posy
authors.forename: Henry
authors.initials: H
authors.lastname: Shen
authors.forename: Neha
authors.initials: N
authors.lastname: Surti
authors.forename: Randy
authors.initials: R
authors.lastname: Talbott
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †Ensemble Therapeutics Corp, 99 Erie Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Terrett
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D005260:Female; D015723:Gene Library; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008958:Models, Molecular; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047028:Macrocyclic Compounds; D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3