title: Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.
abstract: Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors.
authors.affiliation: 1] KINOMEscan Division of DiscoveRx Corporation, San Diego, California, USA. [2].
authors.forename: Pietro
authors.initials: P
authors.lastname: Ciceri
authors.affiliation: 1] Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Oxford, UK. [2] Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Oxford, UK. [3].
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: 1] BioSeek Division of DiscoveRx Corporation, San Francisco, California, USA. [2].
authors.forename: Alison
authors.identifier: 0000000184030351
authors.initials: A
authors.lastname: O'Mahony
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Oxford, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: 1] Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Oxford, UK. [2] Nuffield Department of Clinical Medicine, University of Oxford, Ludwig Institute for Cancer Research (LICR), Oxford, UK.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.affiliation: KINOMEscan Division of DiscoveRx Corporation, San Diego, California, USA.
authors.forename: Jeremy P
authors.identifier: 0000000287973977
authors.initials: JP
authors.lastname: Hunt
authors.affiliation: Division of Hematology/Oncology, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Lasater
authors.affiliation: KINOMEscan Division of DiscoveRx Corporation, San Diego, California, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Pallares
authors.affiliation: 1] Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Oxford, UK. [2] Nuffield Department of Clinical Medicine, University of Oxford, Ludwig Institute for Cancer Research (LICR), Oxford, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.affiliation: 1] Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Oxford, UK. [2] Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Oxford, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wells
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Oxford, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Martin
authors.affiliation: KINOMEscan Division of DiscoveRx Corporation, San Diego, California, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Wodicka
authors.affiliation: Division of Hematology/Oncology, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.affiliation: KINOMEscan Division of DiscoveRx Corporation, San Diego, California, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Treiber
authors.affiliation: 1] Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Oxford, UK. [2] Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Oxford, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000138:chemical synthesis* / Q000494:pharmacology*; D015153:Blotting, Western; D002151:Calorimetry; D045744:Cell Line, Tumor; D003460:Crystallization; D015195:Drug Design; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D044127:Epigenesis, Genetic; D057166:High-Throughput Screening Assays; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D064798:Polypharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011621:Pteridines; D011759:Pyrrolidines; D011994:Recombinant Proteins; D013449:Sulfonamides; C518477:BI 2536; C528327:fedratinib; D000096926:Benzenesulfonamides