Synthesis and biological activity of 1H-pyrrolo[3,2-g]isoquinolines as Haspin kinase inhibitors.

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Haspin (Haspin kinase) is a validated target in oncology.
• Previous studies identified 1H-pyrrolo[3,2-g]isoquinolines as potential Haspin inhibitors.

Purpose of the Study:

• To synthesize and evaluate novel 1H-pyrrolo[3,2-g]isoquinoline derivatives as Haspin inhibitors.
• To develop PROTAC conjugates based on the pyrroloisoquinoline scaffold for targeted protein degradation.
• To identify selective and potent Haspin inhibitors for further investigation.

Main Methods:

• Synthesis of N-alkylated pyrroloisoquinoline conjugates via N-alkylation.
• Synthesis of a carbonylated pyrroloisoquinoline derivative at the 3-position.
• In vitro enzymatic assays to determine Haspin inhibitory potency (IC50) and selectivity.
• Cell-based assays to assess effects on cell viability and cellular Haspin kinase activity.

Main Results:

• None of the synthesized PROTAC conjugates exhibited Haspin inhibitory activity.
• N-methylated derivative 10, substituted with a pyridin-4-yl group at the 3-position, emerged as the most potent and selective Haspin inhibitor in this series.
• Compound 10 displayed an IC50 of 23.6 nM against Haspin and a selectivity index >14 against other kinases.
• This derivative also demonstrated significant inhibitory effects on cellular Haspin kinase and impacted the viability of various human cell lines.

Conclusions:

• The N-methylated pyrroloisoquinoline scaffold can be optimized for potent and selective Haspin inhibition.
• While PROTAC strategies using this scaffold were unsuccessful in this study, potent inhibitors were identified.
• Derivative 10 represents a promising lead compound for further development targeting Haspin in cancer therapy.