title: Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.
abstract: The G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA, de_dios_alfonso@lilly.com.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Gelbert
authors.forename: Shufen
authors.initials: S
authors.lastname: Cai
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.forename: Concepcion
authors.initials: C
authors.lastname: Sanchez-Martinez
authors.forename: Miriam
authors.initials: M
authors.lastname: Del Prado
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Lallena
authors.forename: Raquel
authors.initials: R
authors.lastname: Torres
authors.forename: Rose T
authors.initials: RT
authors.lastname: Ajamie
authors.forename: Graham N
authors.initials: GN
authors.lastname: Wishart
authors.forename: Robert Steven
authors.initials: RS
authors.lastname: Flack
authors.forename: Blake Lee
authors.initials: BL
authors.lastname: Neubauer
authors.forename: Jamie
authors.initials: J
authors.lastname: Young
authors.forename: Edward M
authors.initials: EM
authors.lastname: Chan
authors.forename: Philip
authors.initials: P
authors.lastname: Iversen
authors.forename: Damien
authors.initials: D
authors.lastname: Cronier
authors.forename: Emiko
authors.initials: E
authors.lastname: Kreklau
authors.forename: Alfonso
authors.initials: A
authors.lastname: de Dios
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; D003841:Deoxycytidine; C000590451:abemaciclib; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D000093542:Gemcitabine