Boronic Acid-Containing 3- pyrazolo[4,3-]quinoline Compounds as Dual CLK/ROCK Inhibitors with Anticancer Properties.

The protein kinases CLK and ROCK play key roles in cell growth and migration, respectively, and are potential anticancer targets. ROCK inhibitors have been approved by the FDA for various diseases and CLK inhibitors are currently being trialed in the clinic as anticancer agents. Compounds with polypharmacology are desired, especially in oncology, due to the potential for high efficacy as well as addressing resistance issues.

Non-kinase off-target inhibitory activities of clinically-relevant kinase inhibitors.

Protein kinases are responsible for a myriad of cellular functions, such as cell cycle, apoptosis, and proliferation. Because of this, kinases make excellent targets for therapeutics. During the process to identify clinical kinase inhibitor candidates, kinase selectivity profiles of lead inhibitors are typically obtained.

Discovery of imidazo[1,2-]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.

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

The 3-pyrazolo[4,3-]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 3-pyrazolo[4,3-]quinoline moiety can be tuned, judicious substitution patterns, to selectively inhibit cancer-associated kinases, such as FLT3 and haspin. A first generation 3-pyrazolo[4,3-]quinoline-based haspin inhibitor, HSD972, and FLT3 inhibitor, HSD1169, were previously disclosed as inhibitors of various cancer cell lines.