title: Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis.
abstract: MYCis a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocksMYCexpression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Forest H
authors.initials: FH
authors.lastname: Andrews
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Moores Cancer Center, UC San Diego School of Medicine, La Jolla, CA 92130.|Rady Children's Hospital San Diego, San Diego, CA 92123.
authors.forename: Alok R
authors.initials: AR
authors.lastname: Singh
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Moores Cancer Center, UC San Diego School of Medicine, La Jolla, CA 92130.|Rady Children's Hospital San Diego, San Diego, CA 92123.
authors.forename: Shweta
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Cassandra A
authors.initials: CA
authors.lastname: Smith
authors.affiliation: SignalRx Pharmaceuticals, Inc., San Diego, CA 92130.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Morales
authors.affiliation: SignalRx Pharmaceuticals, Inc., San Diego, CA 92130.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Garlich
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Moores Cancer Center, UC San Diego School of Medicine, La Jolla, CA 92130; ddurden@ucsd.edu Tatiana.Kutateladze@ucdenver.edu.|Rady Children's Hospital San Diego, San Diego, CA 92123.|SignalRx Pharmaceuticals, Inc., San Diego, CA 92130.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Durden
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045; ddurden@ucsd.edu Tatiana.Kutateladze@ucdenver.edu.|Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000556:secondary; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000556:secondary; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000502:physiology; D011714:Pyrans / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009025:Morpholines; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011714:Pyrans; D013876:Thiophenes; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse; C489427:MYC protein, human; C489428:Myc protein, mouse
keywords: BRD4; MYC; PI3K; bromodomain; inhibitor