Dual FLT3/haspin kinase inhibitor based on 3H-pyrazolo[4,3-f]quinoline scaffold with activities against acute myeloid leukemia

Abstract

The 3H-pyrazolo[4,3-f]quinoline core, a privileged fusion moiety from quinoline and indazole, facilely synthesized in a one flask multi-component Doebner–Povarov reaction, is a newly described kinase hinge binder. Previous works have demonstrated that the 3H-pyrazolo[4,3-f]quinoline moiety can be tuned, via judicious substitution patterns, to selectively inhibit cancer-associated kinases, such as FLT3 and haspin. A first generation 3H-pyrazolo[4,3-f]quinoline-based haspin inhibitor, HSD972, and FLT3 inhibitor, HSD1169, were previously disclosed as inhibitors of various cancer cell lines. Given the recent revelation that haspin is over-expressed and plays critical proliferative roles in many cancers, and compounds with dual activity against FLT3 and other important kinases are now being actively developed by many groups, we became interested in optimizing the 3H-pyrazolo[4,3-f]quinoline-based compounds to improve activity against both FLT3 and haspin. Herein, we report the discovery of new 3H-pyrazolo[4,3-f]quinoline-based dual FLT3/haspin inhibitor, HSK205. HSK205 has remarkable potencies against FLT3-driven AML cell lines, inhibiting proliferation with GI₅₀ values between 2–25 nM. Western blot analyses of treated AML cells confirm that HSK205 inhibit the phosphorylation of both FLT3 and histone H3 (a haspin target) in cells. While multi-component reactions (MCRs) have been used to make many bioactive molecules, there are very few examples of using MCRs to make compounds that target protein kinases, which have emerged as one of the top drug candidates (especially in oncology). This work highlights our recent efforts to make ultrapotent protein kinase inhibitors using multi-component reactions (especially the Doebner–Povarov reaction).