title: ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.
abstract: Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA. andrew.souers@abbvie.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.forename: Joel D
authors.initials: JD
authors.lastname: Leverson
authors.forename: Erwin R
authors.initials: ER
authors.lastname: Boghaert
authors.forename: Scott L
authors.initials: SL
authors.lastname: Ackler
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Catron
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dayton
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Sari H
authors.initials: SH
authors.lastname: Enschede
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Hymowitz
authors.forename: Sha
authors.initials: S
authors.lastname: Jin
authors.forename: Seong Lin
authors.initials: SL
authors.lastname: Khaw
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kovar
authors.forename: Lloyd T
authors.initials: LT
authors.lastname: Lam
authors.forename: Jackie
authors.initials: J
authors.lastname: Lee
authors.forename: Heather L
authors.initials: HL
authors.lastname: Maecker
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Kylie D
authors.initials: KD
authors.lastname: Mason
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mitten
authors.forename: Paul M
authors.initials: PM
authors.lastname: Nimmer
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.forename: Chang H
authors.initials: CH
authors.lastname: Park
authors.forename: Cheol-Min
authors.initials: CM
authors.lastname: Park
authors.forename: Darren C
authors.initials: DC
authors.lastname: Phillips
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.forename: Morey L
authors.initials: ML
authors.lastname: Smith
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Sullivan
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Chris
authors.initials: C
authors.lastname: Tse
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wendt
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiao
authors.forename: John C
authors.initials: JC
authors.lastname: Xue
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.forename: Rod A
authors.initials: RA
authors.lastname: Humerickhouse
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D005260:Female; D006367:HeLa Cells; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013449:Sulfonamides / Q000494:pharmacology*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; C579720:venetoclax; C528561:navitoclax