Discovery of imidazo[1,2-b]pyridazine-containing TAK1 kinase inhibitors with excellent activities against multiple myeloma.

Abstract

Current treatment options for patients with multiple myeloma (MM) include proteasome inhibitors, anti-CD38 antibodies, and immunomodulatory agents. However, if patients have continued disease progression after administration of these treatments, there are limited options. There is a need for effective targeted therapies of MM. Recent studies have shown that the transforming growth factor-β activated kinase (TAK1) is upregulated and overexpressed in MM. We have discovered that 6-substituted morpholine or piperazine imidazo[1,2-b]pyridazines, with an appropriate aryl substituent at position-3, inhibit TAK1 at nanomolar concentrations. The lead compound, 26, inhibits the enzymatic activity of TAK1 with an IC50 of 55 nM. Under similar conditions, the known TAK1 inhibitor, takinib, inhibits the kinase with an IC50 of 187 nM. Compound 26 and analogs thereof inhibit the growth of multiple myeloma cell lines MPC-11 and H929 with GI50 values as low as 30 nM. These compounds have the potential to be translated into anti-MM therapeutics.