title: Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors.
abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Michellys
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Yunho
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Wenshuo
authors.initials: W
authors.lastname: Lu
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Marsilje
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Pei
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Uno
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Baogen
authors.initials: B
authors.lastname: Wu
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Truc Ngoc
authors.initials: TN
authors.lastname: Nguyen
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Lee
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Nanxin
authors.initials: N
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Sungjoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Sanofi Oncology, 640 Memorial Drive, Cambridge, MA 02139, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Sun
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
authors.forename: Auzon
authors.initials: A
authors.lastname: Steffy
authors.affiliation: Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Tami
authors.initials: T
authors.lastname: Hood
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives / Q000737:chemistry; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C026805:2,4-diaminopyridine; D015761:4-Aminopyridine; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; Hinge; Karpas299; Scaffold morphing