title: KN-62 analogues as potent differentiating agents of HL-60 cells.
abstract: KN-62, an inhibitor of the calmodulin-dependent protein kinases (CaMKs), enhances the terminal differentiation of retinoic acid sensitive human myeloid leukemia cell lines. In an effort to identify additional CaMK inhibitors that exhibit more potent activity in triggering leukemia cell differentiation, we synthesized 45 analogues of KN-62 and determined their ability to induce HL-60 cell differentiation. Sixteen of these novel analogues exhibited significant differentiation-inducing activity, and one analogue, AS-004, was five times more potent than KN-62 in inhibiting proliferation and inducing differentiation of HL-60 cells. Such KN-62 analogues and/or related compounds may prove useful in treating promyelocytic leukemia.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schuler
authors.forename: Jutong
authors.initials: J
authors.lastname: Si
authors.forename: LeMoyne
authors.initials: L
authors.lastname: Mueller
authors.forename: Julian A
authors.initials: JA
authors.lastname: Simon
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Collins
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells / Q000473:pathology; D006801:Humans; D015394:Molecular Structure
chemical_list: D039481:CD11b Antigen; D004791:Enzyme Inhibitors; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017871:Calcium-Calmodulin-Dependent Protein Kinases