title: Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.
abstract: The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Marsilje
authors.forename: Wei
authors.initials: W
authors.lastname: Pei
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.forename: Wenshuo
authors.initials: W
authors.lastname: Lu
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Uno
authors.forename: Yunho
authors.initials: Y
authors.lastname: Jin
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Sungjoon
authors.initials: S
authors.lastname: Kim
authors.forename: Nanxin
authors.initials: N
authors.lastname: Li
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.forename: Yelena
authors.initials: Y
authors.lastname: Sarkisova
authors.forename: Frank
authors.initials: F
authors.lastname: Sun
authors.forename: Auzon
authors.initials: A
authors.lastname: Steffy
authors.forename: AnneMarie C
authors.initials: AC
authors.lastname: Pferdekamper
authors.forename: Allen G
authors.initials: AG
authors.lastname: Li
authors.forename: Sean B
authors.initials: SB
authors.lastname: Joseph
authors.forename: Young
authors.initials: Y
authors.lastname: Kim
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Cui
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Ruo
authors.initials: R
authors.lastname: Steensma
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Wan
authors.forename: Jiqing
authors.initials: J
authors.lastname: Jiang
authors.forename: Greg
authors.initials: G
authors.lastname: Chopiuk
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: W Perry
authors.initials: WP
authors.lastname: Gordon
authors.forename: Wendy
authors.initials: W
authors.lastname: Richmond
authors.forename: Kevin
authors.initials: K
authors.lastname: Johnson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.forename: Todd
authors.initials: T
authors.lastname: Groessl
authors.forename: You-Qun
authors.initials: YQ
authors.lastname: He
authors.forename: Andrew
authors.initials: A
authors.lastname: Phimister
authors.forename: Alex
authors.initials: A
authors.lastname: Aycinena
authors.forename: Christian C
authors.initials: CC
authors.lastname: Lee
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Michellys
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004285:Dogs; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib