title: Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.
abstract: Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.
authors: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors: Milan
authors: M
authors: Bruncko
authors: Le
authors: L
authors: Wang
authors: George S
authors: GS
authors: Sheppard
authors: Darren C
authors: DC
authors: Phillips
authors: Stephen K
authors: SK
authors: Tahir
authors: John
authors: J
authors: Xue
authors: Scott
authors: S
authors: Erickson
authors: Steve
authors: S
authors: Fidanze
authors: Elizabeth
authors: E
authors: Fry
authors: Lisa
authors: L
authors: Hasvold
authors: Gary J
authors: GJ
authors: Jenkins
authors: Sha
authors: S
authors: Jin
authors: Russell A
authors: RA
authors: Judge
authors: Peter J
authors: PJ
authors: Kovar
authors: David
authors: D
authors: Madar
authors: Paul
authors: P
authors: Nimmer
authors: Chang
authors: C
authors: Park
authors: Andrew M
authors: AM
authors: Petros
authors: Saul H
authors: SH
authors: Rosenberg
authors: Morey L
authors: ML
authors: Smith
authors: Xiaohong
authors: X
authors: Song
authors: Chaohong
authors: C
authors: Sun
authors: Zhi-Fu
authors: ZF
authors: Tao
authors: Xilu
authors: X
authors: Wang
authors: Yu
authors: Y
authors: Xiao
authors: Haichao
authors: H
authors: Zhang
authors: Chris
authors: C
authors: Tse
authors: Joel D
authors: JD
authors: Leverson
authors: Steven W
authors: SW
authors: Elmore
authors: Andrew J
authors: AJ
authors: Souers
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein