4QVX

Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.

Tao, Z.F., Hasvold, L., Wang, L., Wang, X., Petros, A.M., Park, C.H., Boghaert, E.R., Catron, N.D., Chen, J., Colman, P.M., Czabotar, P.E., Deshayes, K., Fairbrother, W.J., Flygare, J.A., Hymowitz, S.G., Jin, S., Judge, R.A., Koehler, M.F., Kovar, P.J., Lessene, G., Mitten, M.J., Ndubaku, C.O., Nimmer, P., Purkey, H.E., Oleksijew, A., Phillips, D.C., Sleebs, B.E., Smith, B.J., Smith, M.L., Tahir, S.K., Watson, K.G., Xiao, Y., Xue, J., Zhang, H., Zobel, K., Rosenberg, S.H., Tse, C., Leverson, J.D., Elmore, S.W., Souers, A.J.

(2014) ACS Med Chem Lett 5: 1088-1093

• PubMed: 25313317 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/ml5001867
• Primary Citation of Related Structures:  
  4QVX


• PubMed Abstract: 
  

  A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.

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Organizational Affiliation: 

AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.