title: Sangivamycin-like molecule 6 exhibits potent anti-multiple myeloma activity through inhibition of cyclin-dependent kinase-9.
abstract: Despite significant treatment advances over the past decade, multiple myeloma (MM) remains largely incurable. In this study we found that MM cells were remarkably sensitive to the death-inducing effects of a new class of sangivamycin-like molecules (SLM). A panel of structurally related SLMs selectively induced apoptosis in MM cells but not other tumor or nonmalignant cell lines at submicromolar concentrations. SLM6 was the most active compound in vivo, where it was well tolerated and significantly inhibited growth and induced apoptosis of MM tumors. We determined that the anti-MM activity of SLM6 was mediated by direct inhibition of cyclin-dependent kinase 9 (CDK9), which resulted in transcriptional repression of oncogenes that are known to drive MM progression (MAF, CCND1, MYC, and others). Furthermore, SLM6 showed superior in vivo anti-MM activity more than the CDK inhibitor flavopiridol, which is currently in clinical trials for MM. These findings show that SLM6 is a novel CDK9 inhibitor with promising preclinical activity as an anti-MM agent.
authors.affiliation: Penn State Milton S. Hershey Medical Center and Cancer Institute, 500 University Drive CH046, Office T4419, Hershey, PA 17033, USA. dolloffn@gmail.com
authors.forename: Nathan G
authors.initials: NG
authors.lastname: Dolloff
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Allen
authors.forename: David T
authors.initials: DT
authors.lastname: Dicker
authors.forename: Nicole
authors.initials: N
authors.lastname: Aqui
authors.forename: Dan
authors.initials: D
authors.lastname: Vogl
authors.forename: Jozef
authors.initials: J
authors.lastname: Malysz
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Talamo
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D009857:Oncogenes; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D011741:Pyrimidine Nucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D014178:Translocation, Genetic; D016896:Treatment Outcome; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011741:Pyrimidine Nucleosides; C580567:sangivamycin-like molecule 6; C005699:sangivamycin; C077990:alvocidib; D000069286:Bortezomib; D042863:Cyclin-Dependent Kinase 9; D014372:Tubercidin