A new class of anti-cancer drugs targeting the tyrosine kinase receptor ROR1 in CLL.

8556 Background: RTK families are attractive therapeutic candidates. One of the families is the ROR receptors. ROR1 is of importance during embryogenesis but down-regulated in most adult human tissues.ROR1 has been shown to be expressed in CLL as well as in other hematological malignancies and solid tumors and is constitutively phosphorylated. ROR1 siRNA transfection of CLL cells induced apoptosis. We have produced and explored the activity of a new class of compounds, acting as inhibitors of phosphorylation of the tyrosine kinase domain of ROR1 (ROR1-TKI). We describe for the first time the activity of a lead ROR-TKI, KAN0439834. Methods: ROR1 inhibitors were derived from a high-through-put screen (HTS) using HTRF assay based on recombinant intracellular kinase domain of ROR1. A chemical lead series was optimized for activity on target, in vitro ADME and in vivo pharmacokinetic properties. Results: KAN0439834 induced apoptosis in vitro of fresh CLL cells from patients with non-progressive and progressive...