Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• Heat shock protein 90 (Hsp90) is crucial for cancer-related protein maturation, making it a key therapeutic target.
• Existing N-terminal Hsp90 inhibitors face challenges due to heat shock response induction.
• C-terminal domain (CTD) inhibition offers an alternative strategy to circumvent this limitation.

Purpose of the Study:

• To design and synthesize novel benzothiazole-based Hsp90 CTD inhibitors.
• To evaluate the antiproliferative activity of these compounds against breast cancer cells.
• To elucidate the structure-activity relationships and binding mechanisms of potent inhibitors.

Main Methods:

• Ligand-based design and structure-based pharmacophore modeling were employed.
• A library of 29 benzothiazole derivatives was synthesized and tested for antiproliferative activity.
• Molecular dynamics simulations were performed to understand the binding mode of lead compounds.

Main Results:

• Several synthesized compounds exhibited low-micromolar IC50 values against MCF-7 breast cancer cells.
• Compounds 5g and 9i demonstrated potent activity with IC50 values of 2.8 ± 0.1 μM and 3.9 ± 0.1 μM, respectively.
• Compound 9i effectively degraded Hsp90 client proteins without inducing the heat shock response.

Conclusions:

• Benzothiazole-based compounds are effective Hsp90 CTD inhibitors.
• The identified compounds represent promising leads for developing novel anticancer agents that avoid heat shock response.
• Further investigation into compound 9i's mechanism and therapeutic potential is warranted.