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.
MeSH terms
-
Anaplastic Lymphoma Kinase
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Drug Design
-
Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
-
Heterocyclic Compounds, 4 or More Rings / chemistry
-
Heterocyclic Compounds, 4 or More Rings / pharmacology
-
Humans
-
Models, Molecular
-
Molecular Conformation
-
Nuclear Proteins / genetics
-
Nucleophosmin
-
Oncogene Proteins, Fusion / genetics
-
Oncogene Proteins, Fusion / metabolism
-
Phosphorylation
-
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
-
Receptor Protein-Tyrosine Kinases / genetics
-
Receptor Protein-Tyrosine Kinases / metabolism
-
Receptor, Insulin / antagonists & inhibitors
-
Structure-Activity Relationship
Substances
-
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
-
Antineoplastic Agents
-
Heterocyclic Compounds, 4 or More Rings
-
Nuclear Proteins
-
Oncogene Proteins, Fusion
-
Nucleophosmin
-
ALK protein, human
-
Anaplastic Lymphoma Kinase
-
Receptor Protein-Tyrosine Kinases
-
Receptor, Insulin