title: Discovery of XL413, a potent and selective CDC7 inhibitor.
abstract: CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
authors.affiliation: Exelixis, Department of Drug Discovery, South San Francisco, CA 94080, USA. elena@numerate.com
authors.forename: Elena S
authors.initials: ES
authors.lastname: Koltun
authors.forename: Amy Lew
authors.initials: AL
authors.lastname: Tsuhako
authors.forename: David S
authors.initials: DS
authors.lastname: Brown
authors.forename: Naing
authors.initials: N
authors.lastname: Aay
authors.forename: Arlyn
authors.initials: A
authors.lastname: Arcalas
authors.forename: Vicky
authors.initials: V
authors.lastname: Chan
authors.forename: Hongwang
authors.initials: H
authors.lastname: Du
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.forename: Kim
authors.initials: K
authors.lastname: Ferguson
authors.forename: Maurizio
authors.initials: M
authors.lastname: Franzini
authors.forename: Adam
authors.initials: A
authors.lastname: Galan
authors.forename: Charles R
authors.initials: CR
authors.lastname: Holst
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: Brian
authors.initials: B
authors.lastname: Kane
authors.forename: Moon H
authors.initials: MH
authors.lastname: Kim
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Markby
authors.forename: Manisha
authors.initials: M
authors.lastname: Mohan
authors.forename: Kevin
authors.initials: K
authors.lastname: Noson
authors.forename: Arthur
authors.initials: A
authors.lastname: Plonowski
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Richards
authors.forename: Scott
authors.initials: S
authors.lastname: Robertson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Shaw
authors.forename: Gordon
authors.initials: G
authors.lastname: Stott
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Stout
authors.forename: Jenny
authors.initials: J
authors.lastname: Young
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
authors.forename: Cristiana A
authors.initials: CA
authors.lastname: Zaharia
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Peiwen
authors.initials: P
authors.lastname: Zhou
authors.forename: John M
authors.initials: JM
authors.lastname: Nuss
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Kearney
mesh_terms: D000818:Animals; D001665:Binding Sites; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; C574818:XL413 compound; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases