ALKYNYL AMINOISOQUINOLINES, NOVEL FLT3 KINASE INHIBITORS WITH POTENT ACTIVITY AGAINST ACUTE MYELOID LEUKEMIA

Abstract

Acute myeloid leukemia (AML) is a type of blood cancer. If not properly treated, this subclass of leukemia can progress quickly, and be fatal after a few months. Aberrantly expressed FMS (Feline McDonough Sarcoma)-like tyrosine kinase (FLT3) is observed in approximately 30% of AML patients, so it is a promising molecular target for AML. Midostaurin (commercial name, Rydapt) was the first approved FDA drug for AML that targets FLT3. However, Midostaurin, is not a single agent drug and is only effective when used in combination with other cytotoxic drugs. Therefore, there is a need for FLT3 inhibitors that are effective as a single agent.

In Chapter 2, the synthesis of a series of amidine-acetylene-isoquinoline-3-amines is described. Amidine-acetylene-isoquinoline-3-amine compounds have the potential to serve new FLT3 inhibitors with inhibition IC50 values in the nanomolar region against wild type FLT3, FLT3-ITD (internal tandem duplications) and FLT3-D835Y (a tyrosine kinase domain mutant, commonly found in AML patients).

Amidine drugs are generally not orally bioavailable, the synthesis of amide-acetylene-isoquinoline-3-amines, our second generation FLT3 inhibitors are described in Chapters 3 and 4. The amide-acetylene-isoquinolines inhibit FLT3-driven AML cell lines with single digit nanomolar IC50 values and are either comparable to or better than most FLT3 inhibitors reported to date.