Discovery of a potent and selective BCL-XL inhibitor with in vivo activity Academic Article uri icon

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.

authors

  • Tao, Z-F
  • Hasvold, L
  • Wang, L
  • Wang, X
  • Petros, AM
  • Park, CH
  • Boghaert, ER
  • Catron, ND
  • Chen, J
  • Colman, PM
  • Czabotar, PE
  • Deshayes, K
  • Fairbrother, WJ
  • Flygare, JA
  • Hymowitz, SG
  • Jin, S
  • Judge, RA
  • Koehler, MFT
  • Kovar, PJ
  • Lessene, G
  • Mitten, MJ
  • Ndubaku, CO
  • Nimmer, P
  • Purkey, HE
  • Oleksijew, A
  • Phillips, DC
  • Sleebs, BE
  • Smith, Brian
  • Smith, ML
  • Tahir, SK
  • Watson, KG
  • Xiao, Y
  • Xue, J
  • Zhang, H
  • Zobel, K
  • Rosenberg, SH
  • Tse, C
  • Leverson, JD
  • Elmore, SW
  • Souers, AJ

publication date

  • 2014