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Zhang Y, Seigal BA, Terrett NK, et al. Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer. ACS Med Chem Lett. 2015;6(7):770-5doi: 10.1021/acsmedchemlett.5b00091.
Zhang, Y., Seigal, B. A., Terrett, N. K., Talbott, R. L., Fargnoli, J., Naglich, J. G., Chaudhry, C., Posy, S. L., Vuppugalla, R., Cornelius, G., Lei, M., Wang, C., Zhang, Y., Schmidt, R. J., Wei, D. D., Miller, M. M., Allen, M. P., Li, L., Carter, P. H., Vite, G. D., & Borzilleri, R. M. (2015). Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer. ACS medicinal chemistry letters, 6(7), 770-5. https://doi.org/10.1021/acsmedchemlett.5b00091
Zhang, Yong, et al. "Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer." ACS medicinal chemistry letters vol. 6,7 (2015): 770-5. doi: https://doi.org/10.1021/acsmedchemlett.5b00091
Zhang Y, Seigal BA, Terrett NK, Talbott RL, Fargnoli J, Naglich JG, Chaudhry C, Posy SL, Vuppugalla R, Cornelius G, Lei M, Wang C, Zhang Y, Schmidt RJ, Wei DD, Miller MM, Allen MP, Li L, Carter PH, Vite GD, Borzilleri RM. Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer. ACS Med Chem Lett. 2015 May 27;6(7):770-5. doi: 10.1021/acsmedchemlett.5b00091. eCollection 2015 Jul 09. PMID: 26191364; PMCID: PMC4499820.
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ACS Med Chem Lett. 2015 May 27;6(7):770-5. doi: 10.1021/acsmedchemlett.5b00091. eCollection 2015 Jul 09.

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

ACS medicinal chemistry letters

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

Affiliations

  1. Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
  2. Ensemble Therapeutics Corp. , 99 Erie Street, Cambridge, Massachusetts 02139, United States.

PMID: 26191364 PMCID: PMC4499820 DOI: 10.1021/acsmedchemlett.5b00091

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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