title: 7,8-dichloro-1-oxo-β-carbolines as a versatile scaffold for the development of potent and selective kinase inhibitors with unusual binding modes.
abstract: Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-β-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Huber
authors.forename: Laurent
authors.initials: L
authors.lastname: Brault
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Christelle
authors.initials: C
authors.lastname: Gasser
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Jörg
authors.initials: J
authors.lastname: Trappe
authors.forename: Jürg
authors.initials: J
authors.lastname: Schwaller
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D047428:Protein Kinase Inhibitors; C087545:bauerine C