title: A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models.
abstract: DNA-dependent RNA polymerase II (RNAP II) largest subunit RPB1 C-terminal domain (CTD) kinases, including CDK9, are serine/threonine kinases known to regulate transcriptional initiation and elongation by phosphorylating Ser 2, 5, and 7 residues on CTD. Given the reported dysregulation of these kinases in some cancers, we asked whether inhibiting CDK9 may induce stress response and preferentially kill tumor cells. Herein, we describe a potent CDK9 inhibitor, LY2857785, that significantly reduces RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines. This molecule inhibits the growth of a broad panel of cancer cell lines, and is particularly efficacious in leukemia cells, including orthotopic leukemia preclinical models as well as in ex vivo acute myeloid leukemia and chronic lymphocytic leukemia patient tumor samples. Thus, inhibition of CDK9 may represent an interesting approach as a cancer therapeutic target, especially in hematologic malignancies.
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Tinggui
authors.initials: T
authors.lastname: Yin
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Lallena
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Emiko L
authors.initials: EL
authors.lastname: Kreklau
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Fales
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Santiago
authors.initials: S
authors.lastname: Carballares
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Raquel
authors.initials: R
authors.lastname: Torrres
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Graham N
authors.initials: GN
authors.lastname: Wishart
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Rose T
authors.initials: RT
authors.lastname: Ajamie
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Damien M
authors.initials: DM
authors.lastname: Cronier
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Iversen
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Timothy I
authors.initials: TI
authors.lastname: Meier
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Foreman
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Douglas
authors.initials: D
authors.lastname: Zeckner
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Sissons
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Bart W
authors.initials: BW
authors.lastname: Halstead
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Aimee B
authors.initials: AB
authors.lastname: Lin
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Donoho
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Yuewei
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Li
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Amit
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Xiang S
authors.initials: XS
authors.lastname: Ye
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: James J
authors.initials: JJ
authors.lastname: Starling
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gaynor
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom du_jian@lilly.com de_dios_alfonso@lilly.com.
authors.forename: Alfonso
authors.initials: A
authors.lastname: de Dios
authors.affiliation: Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom du_jian@lilly.com de_dios_alfonso@lilly.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Du
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics*; D003514:Cyclohexylamines / Q000008:administration & dosage*; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage*; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D007191:Indazoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C000595237:N1-(4-(3-isopropyl-2-methylindazol-5-yl)pyrimidin-2-yl)-N4-tetrahydropyran-4-yl-cyclohexane-1,4-diamine; D012694:Serine; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9