Discovery of Potent MyeloidCell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods andStructure-Based Design.
- Resource Type
- Article
- Authors
- Friberg, Anders; Vigil, Dominico; Zhao, Bin; Daniels, R. Nathan; Burke, Jason P.; Garcia-Barrantes, Pedro M.; Camper, De Marco; Chauder, Brian A.; Lee, Taekyu; Olejniczak, Edward T.; Fesik, Stephen W.
- Source
- Journal of Medicinal Chemistry. Vol. 56 Issue 1, p15-30. 16p.
- Subject
- *DRUG development
*ANTINEOPLASTIC agents
*STRUCTURAL optimization
*LEUKEMIA treatment
*MYELOID leukemia
*BCL-2 proteins
*GENE expression
*COCARCINOGENESIS
*APOPTOSIS
- Language
- ISSN
- 0022-2623
Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2family of proteins, is overexpressed and amplified in various cancersand promotes the aberrant survival of tumor cells that otherwise wouldundergo apoptosis. Here we describe the discovery of potent and selectiveMcl-1 inhibitors using fragment-based methods and structure-baseddesign. NMR-based screening of a large fragment library identifiedtwo chemically distinct hit series that bind to different sites onMcl-1. Members of the two fragment classes were merged together toproduce lead compounds that bind to Mcl-1 with a dissociation constantof <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structuresof merged compounds when complexed to Mcl-1 were obtained by X-raycrystallography and provide detailed information about the molecularrecognition of small-molecule ligands binding Mcl-1. The compoundsrepresent starting points for the discovery of clinically useful Mcl-1inhibitors for the treatment of a wide variety of cancers. [ABSTRACT FROM AUTHOR]