Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations

• DOI: 10.1038/s41467-019-10363-1
• Publication Date: 2019-06-03T10:22:43Z
• Authors: Richard W. Birkin...; Jia-nan Gong; Cindy S. Luo; Daisy Lio; Christine A. White; Mary Ann Anderson; Piers Blombery; Guillaume Lessene; Ian J. Majewski; Rachel Thijssen; Andrew W. Roberts; David C. S. Huang; Peter M. Colman; Peter E. Czabotar
• Keywords: Venetoclax

Abstract Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia this BCL-2 antagonist has revealed emergence drug-selected mutation (G101V) in some failing therapy. To understand molecular basis acquired resistance we describe crystal structures venetoclax bound to both and G101V mutant. The pose its binding site on reveals small but unexpected differences as compared published complexes analogues. mutant complex structure assays reveal by knock-on effect V101 an adjacent residue, E152, restored E152A mutation. This provides framework for considering analogues might be effective combating