title: Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity.
abstract: ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Brad E
authors.initials: BE
authors.lastname: Sleebs
authors.forename: Peter E
authors.initials: PE
authors.lastname: Czabotar
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Fairlie
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Wilhelmus J A
authors.initials: WJ
authors.lastname: Kersten
authors.forename: Michael F T
authors.initials: MF
authors.lastname: Koehler
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lessene
authors.forename: Kym
authors.initials: K
authors.lastname: Lowes
authors.forename: John P
authors.initials: JP
authors.lastname: Parisot
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Morey L
authors.initials: ML
authors.lastname: Smith
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.forename: Ian P
authors.initials: IP
authors.lastname: Street
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
mesh_terms: D000818:Animals; D017209:Apoptosis; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D013449:Sulfonamides; D051020:bcl-X Protein