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

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-ß 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.

Identification of a Selective FLT3 Inhibitor with Low Activity against VEGFR, FGFR, PDGFR, c-KIT, and RET Anti-Targets.

FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential target for treating chronic pain. Most FLT3 inhibitors (FLT3i) identified to date, including approved drugs such as gilteritinib, midostaurin, ponatinib, quizartinib, and FLT3i in clinical trials, such as quizartinib and crenolanib, also inhibit closely-related kinases that are important for immune (c-KIT), cardiovascular (KDR/VEGFR2, FGFR, PDGFR) or kidney (RET) functions. While the aforementioned FLT3i may increase survival rates in AML, they are neither ideal for AML maintenance therapy nor for non-oncology applications, such as for the treatment of chronic pain, due to their promiscuous inhibition of many kinase anti-targets. Here, we report the identification of new FLT3i compounds that have low activities against kinases that have traditionally been difficult to differentiate from FLT3 inhibition, such as KDR/VEGFR, FGFR, PGFR, c-KIT, and RET. These selective compounds could be valuable chemical probes for studying FLT3 biology in the context of chronic pain and/or may represent good starting points to develop well-tolerated FLT3 therapeutics for non-oncology indications or for maintenance therapy for AML.