2-Thioxothiazolidin-4-one Analogs as Pan-PIM Kinase Inhibitors

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Proviral integration site for Moloney murine leukemia virus (PIM) kinases are proto-oncogenic kinases implicated in regulating key cellular processes.
• PIM kinases are integral to cancer-specific pathways, including survival, apoptosis, proliferation, cell cycle regulation, and migration, making them attractive drug targets.

Purpose of the Study:

• To synthesize and evaluate novel 2-thioxothiazolidin-4-one derivatives as potent pan-PIM kinase inhibitors.
• To assess the selectivity and efficacy of these compounds against PIM kinases and cancer cell lines.

Main Methods:

• Synthesis of a series of 2-thioxothiazolidin-4-one derivatives.
• In vitro kinase inhibition assays to determine IC50 values against PIM kinases.
• Selectivity profiling against a panel of 14 other kinases.
• Cell-based assays to evaluate compound efficacy (EC50) and target modulation in cancer cell lines.

Main Results:

• Optimized compounds demonstrated single-digit nanomolar IC50 values against all three PIM kinase isoforms.
• High selectivity was observed for the developed compounds over 14 other kinases.
• Compound 17 effectively inhibited Molm-16 cell line growth (EC50 = 14 nM) and dose-dependently modulated pBAD and p4EBP1 expression.

Conclusions:

• 2-thioxothiazolidin-4-one derivatives represent a promising class of potent and selective pan-PIM kinase inhibitors.
• These findings support the therapeutic potential of targeting PIM kinases for cancer treatment.
• Compound 17 shows significant preclinical activity warranting further investigation.