title: Pharmacologic properties of AG-012986, a pan-cyclin-dependent kinase inhibitor with antitumor efficacy.
abstract: AG-012986 is a multitargeted cyclin-dependent kinase (CDK) inhibitor active against CDK1, CDK2, CDK4/6, CDK5, and CDK9, with selectivity over a diverse panel of non-CDK kinases. Here, we report the potent antitumor efficacies of AG-012986 against multiple tumor lines in vitro and in vivo. AG-012986 showed antiproliferative activities in vitro with IC(50)s of <100 nmol/L in 14 of 18 tumor cell lines. In vivo, significant antitumor efficacy induced by AG-012986 was seen (tumor growth inhibition, >83.1%) in 10 of 11 human xenograft tumor models when administered at or near the maximum tolerated dose for 8 or 12 days. AG-012986 caused dose-dependent hypophosphorylation at Ser(795) of the retinoblastoma protein, cell cycle arrest, and apoptosis in vitro. Colony-forming assays indicated that the potency of AG-012986 substantially decreased with treatment time of <24 h. In vivo, AG-012986 also showed dose-dependent retinoblastoma Ser(795) hypophosphorylation, cell cycle arrest, decreased Ki-67 tumor staining, and apoptosis in conjunction with antitumor activity. Studies comparing i.p. bolus with s.c. implanted minipump dosing regimens revealed that in vivo efficacy correlated with the duration of minimally effective plasma levels rather than maximal drug plasma levels. Dosing optimization of AG-012986 provided guidance for selecting a treatment schedule to achieve the best antitumor efficacy while minimizing the risk of adverse side effects.
authors.affiliation: Department of Cancer Biology, Pfizer Global Research and Development, 10724 Science Center Road, San Diego, CA 92121, USA. cathy.zhang@pfizer.com
authors.forename: Cathy
authors.initials: C
authors.lastname: Zhang
authors.forename: Karen
authors.initials: K
authors.lastname: Lundgren
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Yan
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arango
authors.forename: Sharon
authors.initials: S
authors.lastname: Price
authors.forename: Andrea
authors.initials: A
authors.lastname: Huber
authors.forename: Joseph
authors.initials: J
authors.lastname: Higgins
authors.forename: Gabriel
authors.initials: G
authors.lastname: Troche
authors.forename: Judith
authors.initials: J
authors.lastname: Skaptason
authors.forename: Tatiana
authors.initials: T
authors.lastname: Koudriakova
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Michelle
authors.initials: M
authors.lastname: Yang
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Connor
authors.forename: Steve
authors.initials: S
authors.lastname: Bender
authors.forename: Gerrit
authors.initials: G
authors.lastname: Los
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Bart
authors.initials: B
authors.lastname: Jessen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003114:Colony-Forming Units Assay; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C512484:AG-012986; D000970:Antineoplastic Agents; D001549:Benzamides; D016160:Retinoblastoma Protein; D013844:Thiazoles; D018844:Cyclin-Dependent Kinases