Synthesis, structure-activity relationship, and p210bcr-abl protein tyrosine kinase activity of novel AG 957 analogs

A series of novel, sterically hindered lipophilic analogs of AG 957 were designed and synthesized as potential protein tyrosine kinase (PTK) inhibitors. Adaphostin (NSC 680410) showed cell growth inhibition both in vitro and in vivo while maintaining the p210bcr-abl autokinase activity. Plasma clearance rate of adaphostin was lower than the parent compound resulting in an increase in the mean residence time. Adaphostin (NSC 680410) has emerged as the improved compound with the maximum in vivo anti-leukemia hollow fiber activity.