Design, synthesis and activity of BBI608 derivatives targeting on stem cells

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Pharmacology

Background:

• Signal transducer and activator of transcription 3 (STAT3) is crucial for tumor stem cell self-renewal.
• BBI608 inhibits STAT3-driven transcription and cancer stemness but requires pharmacokinetic and activity improvements.
• Developing novel STAT3 inhibitors is essential for effective cancer therapy.

Purpose of the Study:

• To design and synthesize novel BBI608 derivatives with enhanced pharmacokinetic properties and antitumor activity.
• To identify potent and selective STAT3 inhibitors for cancer treatment.
• To evaluate the efficacy of new compounds against cancer stemness.

Main Methods:

• Synthesis of a series of BBI608 derivatives.
• In vitro evaluation of inhibitory activity against HepG2 cancer cells and L-02 normal liver cells.
• Assessment of IC50 values and selectivity.
• Evaluation of ClogP and water solubility for lead compound optimization.

Main Results:

• Several BBI608 derivatives exhibited enhanced potency compared to BBI608 against HepG2 cells.
• Compound LD-8 showed the highest potency but lacked selectivity.
• Compounds LD-17 and LD-19 displayed significant inhibitory activity and good selectivity.
• LD-19 demonstrated potent activity, favorable ClogP, and improved water solubility.

Conclusions:

• BBI608 derivatives offer improved therapeutic potential over the parent compound.
• Compound LD-19 is a promising lead candidate for further preclinical development due to its potent activity and favorable physicochemical properties.
• Targeting STAT3 remains a viable strategy for inhibiting cancer stemness and treating various cancers.