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

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Cyclin-dependent kinase (CLK) and Rho-associated protein kinase (ROCK) are key targets in cancer therapy.
• Existing ROCK inhibitors are FDA-approved, and CLK inhibitors are in clinical trials.
• Polypharmacology, targeting multiple pathways, is crucial for enhanced efficacy and overcoming resistance in cancer treatment.

Purpose of the Study:

• To identify and characterize novel boron-containing dual inhibitors of CLK and ROCK kinases.
• To evaluate the anticancer properties of these novel compounds against various cancer cell lines.

Main Methods:

• Synthesis of boronic acid-based CLK/ROCK inhibitors using Povarov/Doebner multicomponent reactions.
• Kinase inhibition screening, cancer cell viability assays, and docking studies to identify and understand lead compounds.
• Cell cycle analysis, qPCR, and immunoblotting to elucidate the mechanism of action.

Main Results:

• Compounds HSD1400 and HSD1791 demonstrated potent inhibition of CLK1, CLK2, and ROCK2 kinases.
• Significant inhibition of renal cancer and leukemia cell growth was observed.
• Compounds induced DNA damage (upregulation of p-H2AX) and cell cycle arrest, with HSD1791 suppressing the cyclin D/Rb pathway.

Conclusions:

• Novel pyrazolo[4,3-f]quinoline-based dual CLK/ROCK inhibitors containing boron were successfully identified.
• The 'magic methylation' strategy effectively tuned CLK selectivity.
• Lead compounds exhibit potent in vitro anticancer activity against renal cancer and leukemia, highlighting the therapeutic potential of boron-containing compounds.