title: Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.
abstract: Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.
authors.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
authors.forename: Milan
authors.initials: M
authors.lastname: Bruncko
authors.forename: Thorsten K
authors.initials: TK
authors.lastname: Oost
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Belli
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Mary K
authors.initials: MK
authors.lastname: Joseph
authors.forename: Aaron
authors.initials: A
authors.lastname: Kunzer
authors.forename: Darlene
authors.initials: D
authors.lastname: Martineau
authors.forename: William J
authors.initials: WJ
authors.lastname: McClellan
authors.forename: Michael
authors.initials: M
authors.lastname: Mitten
authors.forename: Shi-Chung
authors.initials: SC
authors.lastname: Ng
authors.forename: Paul M
authors.initials: PM
authors.lastname: Nimmer
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: Cheol-Min
authors.initials: CM
authors.lastname: Park
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shoemaker
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Song
authors.forename: Xilu
authors.initials: X
authors.lastname: Wang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wendt
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008223:Lymphoma; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009596:Nitrophenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein