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Start Over Author "Zheng Xiaolan" Journal acs medicinal chemistry letters
4 results on '"Zheng Xiaolan"'

1. Correction to “Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors”

Author

Johannes, Jeffrey W., primary, Bates, Stephanie, additional, Beigie, Carl, additional, Belmonte, Matthew A., additional, Breen, John, additional, Cao, Shenggen, additional, Centrella, Paolo A., additional, Clark, Matthew A., additional, Cuozzo, John W., additional, Dumelin, Christoph E., additional, Ferguson, Andrew D., additional, Habeshian, Sevan, additional, Hargreaves, David, additional, Joubran, Camil, additional, Kazmirski, Steven, additional, Keefe, Anthony D., additional, Lamb, Michelle L., additional, Lan, Haiye, additional, Li, Yunxia, additional, Ma, Hao, additional, Mlynarski, Scott, additional, Packer, Martin J., additional, Rawlins, Philip B., additional, Robbins, Daniel W., additional, Shen, Haidong, additional, Sigel, Eric A., additional, Soutter, Holly H., additional, Su, Nancy, additional, Troast, Dawn M., additional, Wang, Haiyun, additional, Wickson, Kate F., additional, Wu, Chengyan, additional, Zhang, Ying, additional, Zhao, Qiuying, additional, Zheng, Xiaolan, additional, and Hird, Alexander W., additional

Published
2017
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2. Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors

Author

Johannes, Jeffrey W., primary, Bates, Stephanie, additional, Beigie, Carl, additional, Belmonte, Matthew A., additional, Breen, John, additional, Cao, Shenggen, additional, Centrella, Paolo A., additional, Clark, Matthew A., additional, Cuozzo, John W., additional, Dumelin, Christoph E., additional, Ferguson, Andrew D., additional, Habeshian, Sevan, additional, Hargreaves, David, additional, Joubran, Camil, additional, Kazmirski, Steven, additional, Keefe, Anthony D., additional, Lamb, Michelle L., additional, Lan, Haiye, additional, Li, Yunxia, additional, Ma, Hao, additional, Mlynarski, Scott, additional, Packer, Martin J., additional, Rawlins, Philip B., additional, Robbins, Daniel W., additional, Shen, Haidong, additional, Sigel, Eric A., additional, Soutter, Holly H., additional, Su, Nancy, additional, Troast, Dawn M., additional, Wang, Haiyun, additional, Wickson, Kate F., additional, Wu, Chengyan, additional, Zhang, Ying, additional, Zhao, Qiuying, additional, Zheng, Xiaolan, additional, and Hird, Alexander W., additional

Published
2017
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3. Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and Wnt Pathway Inhibitors Suitable for in Vivo Pharmacology

Author

Johannes, Jeffrey W., primary, Almeida, Lynsie, additional, Barlaam, Bernard, additional, Boriack-Sjodin, P. Ann, additional, Casella, Robert, additional, Croft, Rosemary A., additional, Dishington, Allan P., additional, Gingipalli, Lakshmaiah, additional, Gu, Chungang, additional, Hawkins, Janet L., additional, Holmes, Jane L., additional, Howard, Tina, additional, Huang, Jian, additional, Ioannidis, Stephanos, additional, Kazmirski, Steven, additional, Lamb, Michelle L., additional, McGuire, Thomas M., additional, Moore, Jane E., additional, Ogg, Derek, additional, Patel, Anil, additional, Pike, Kurt G., additional, Pontz, Timothy, additional, Robb, Graeme R., additional, Su, Nancy, additional, Wang, Haiyun, additional, Wu, Xiaoyun, additional, Zhang, Hai-Jun, additional, Zhang, Yue, additional, Zheng, Xiaolan, additional, and Wang, Tao, additional

Published
2015
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4. Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors.

Author

Johannes JW, Bates S, Beigie C, Belmonte MA, Breen J, Cao S, Centrella PA, Clark MA, Cuozzo JW, Dumelin CE, Ferguson AD, Habeshian S, Hargreaves D, Joubran C, Kazmirski S, Keefe AD, Lamb ML, Lan H, Li Y, Ma H, Mlynarski S, Packer MJ, Rawlins PB, Robbins DW, Shen H, Sigel EA, Soutter HH, Su N, Troast DM, Wang H, Wickson KF, Wu C, Zhang Y, Zhao Q, Zheng X, and Hird AW

Abstract

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1 , a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4-11 cells with an IC 50 of 3 μM after 6 h., Competing Interests: The authors declare no competing financial interest.

Published
2016
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