title: Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2,4,8,22-tetraazatetracyclo[14.3.1.1³,⁷.1⁹,¹³]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles.
abstract: A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC(50) = 0.5 nM) and cellular (IC(50) = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted "U" shaped conformation of the acyclic DAPs is a preferred bioactive conformation.
authors.affiliation: Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380-4245, United States. HBreslin60@gmail.com
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Breslin
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Lane
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Ott
authors.forename: Arup K
authors.initials: AK
authors.lastname: Ghose
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
authors.forename: Weihua
authors.initials: W
authors.lastname: Wan
authors.forename: R Curtis
authors.initials: RC
authors.lastname: Haltiwanger
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wells-Knecht
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C570918:6-chloro-10-(2-methanesulfonylmethylamino)-17-(4-methylpiperazin-1-yl)-19-methoxy-2,4,8,22-tetraazatetracyclo(14.3.1.13,7.19,13)docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000090243:Nucleophosmin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D011972:Receptor, Insulin