WHI-P258

Description: WHI-P258 is a potent and selective Janus kinase 3 (JAK3) inhibitor discovered from homology modeling. Potent and specific inhibitors of JAK3 such as WHI-P131 may provide the basis for the design of new treatment strategies against acute lymphoblastic leukemia, the most common form of childhood cancer. WHI-P258 was identified from a novel homology model of the kinase domain of Janus kinase (JAK) 3 used for the structure-based design of dimethoxyquinazoline compounds with potent and specific inhibitory activity against JAK3. The active site of JAK3 in this homology model measures roughly 8 A x 11 A x 20 A, with a volume of approximately 530 A3 available for inhibitor binding. Modeling studies indicated that WHI-258 would likely fit into the catalytic site of JAK3 and that derivatives of this compound that contain an OH group at the 4' position of the phenyl ring would more strongly bind to JAK3 because of added interactions with Asp-967, a key residue in the catalytic site of JAK3.

References: Clin Cancer Res. 1999 Jun; 5(6):1569-82.