title: Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer.
abstract: A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
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: Nicholas K
authors.initials: NK
authors.lastname: Terrett
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Talbott
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Naglich
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Charu
authors.initials: C
authors.lastname: Chaudhry
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Shana L
authors.initials: SL
authors.lastname: Posy
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Ragini
authors.initials: R
authors.lastname: Vuppugalla
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Georgia
authors.initials: G
authors.lastname: Cornelius
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wang
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Yingru
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmidt
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Wei
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Miller
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Allen
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
keywords: Inhibitor of apoptosis proteins (IAPs); cancer; dimeric macrocyclic antagonists