title: Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL.
abstract: Proteolysis Targeting Chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTAC technology employs small molecules that recruit target proteins for ubiquitination and removal by the proteasome. The synthesis of PROTAC compounds that mediate the degradation of c-ABL and BCR-ABL by recruiting either Cereblon or Von Hippel Lindau E3 ligases is reported. During the course of their development, we discovered that the capacity of a PROTAC to induce degradation involves more than just target binding: the identity of the inhibitor warhead and the recruited E3 ligase largely determine the degradation profiles of the compounds; thus, as a starting point for PROTAC development, both the target ligand and the recruited E3 ligase should be varied to rapidly generate a PROTAC with the desired degradation profile.
authors.affiliation: Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA).
authors.forename: Ashton C
authors.initials: AC
authors.lastname: Lai
authors.affiliation: Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA).
authors.forename: Momar
authors.initials: M
authors.lastname: Toure
authors.affiliation: Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA).
authors.forename: Doris
authors.initials: D
authors.lastname: Hellerschmied
authors.affiliation: Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA).
authors.forename: Jemilat
authors.initials: J
authors.lastname: Salami
authors.affiliation: Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA).
authors.forename: Saul
authors.initials: S
authors.lastname: Jaime-Figueroa
authors.affiliation: Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA).
authors.forename: Eunhwa
authors.initials: E
authors.lastname: Ko
authors.affiliation: Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA).
authors.forename: John
authors.initials: J
authors.lastname: Hines
authors.affiliation: Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA). craig.crews@yale.edu.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D059748:Proteolysis
chemical_list: D016044:Fusion Proteins, bcr-abl
keywords: E3 ubiquitin ligases; cancer; drug design; inhibitors; protein degradation