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. 2015 May 27;6(7):770-5.
doi: 10.1021/acsmedchemlett.5b00091. eCollection 2015 Jul 9.

Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer

Yong Zhang  1 , Benjamin A Seigal  2 , Nicholas K Terrett  2 , Randy L Talbott  1 , Joseph Fargnoli  1 , Joseph G Naglich  1 , Charu Chaudhry  1 , Shana L Posy  1 , Ragini Vuppugalla  1 , Georgia Cornelius  1 , Ming Lei  1 , Chunlei Wang  1 , Yingru Zhang  1 , Robert J Schmidt  1 , Donna D Wei  1 , Michael M Miller  1 , Martin P Allen  1 , Ling Li  1 , Percy H Carter  1 , Gregory D Vite  1 , Robert M Borzilleri  1
Affiliations

Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer

Yong Zhang et al. ACS Med Chem Lett. .

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.

Keywords: Inhibitor of apoptosis proteins (IAPs); cancer; dimeric macrocyclic antagonists.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Binding model of compound 1 in the Bir2-3 domains of XIAP protein. Carbon atoms of 1 are in green. Oxygen and nitrogen atoms are highlighted in red and blue, respectively. The protein surface is represented by electrostatic potential.
Scheme 1
Scheme 1. (a) EDCI, HOAt, NMM, DMF; (b) TFA, DCM; (c) Boc-t-L-Leucine, EDCI, HOAt, NMM, DMF; (d) TFA, DCM; (e) Boc-N-methyl-L-Alanine, EDCI, HOAt, NMM, DMF; (f) aq. LiOH, THF; (g) HATU, NMM, DMF; (h) CuSO4, sodium ascorbic acid, THF/tBuOH/H2O; (i) Hoveyda-Grubbs II catalyst, DCE, 70 °C; (j) TFA, DCM; (k) Pd/C, H2, MeOH
Figure 2
Figure 2
Antitumor activity of 11 in the A875 xenograft model in mice. Compounds were administered intraperitoneally (i.p.) every 3 days for six doses or weekly for two doses beginning on day 10.
See this image and copyright information in PMC

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