title: Towards the next generation of dual Bcl-2/Bcl-xL inhibitors.
abstract: Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: Jeffrey.Varnes@Astrazeneca.com.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Varnes
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gero
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Diebold
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Claude
authors.initials: C
authors.lastname: Ogoe
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Grover
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Su
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Mukherjee
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Jamal Carlos
authors.initials: JC
authors.lastname: Saeh
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: MacIntyre
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Repik
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Dillman
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Byth
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Daniel John
authors.initials: DJ
authors.lastname: Russell
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Stephanos
authors.initials: S
authors.lastname: Ioannidis
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; C528561:navitoclax
keywords: Apoptosis; B-cell lymphoma; Bcl-2; Bcl-x(L); Navitoclax