NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure-Activity Insights

Area of Science:

• Biochemistry
• Pharmacology
• Drug Discovery

Background:

• Microtubule targeting agents (MTAs) are crucial in cancer therapy, binding to tubulin to inhibit cancer cell proliferation.
• Despite existing MTAs, there is a continuous need for novel, effective anticancer compounds.
• Current screening methods for MTAs can be limited in scope and efficiency.

Purpose of the Study:

• To develop and validate an innovative in vitro screening methodology for MTAs using nano-differential scanning fluorimetry (nanoDSF).
• To assess compound-tubulin binding and quantitatively analyze the impact on tubulin polymerization.
• To facilitate the discovery of novel structure-activity relationships (SAR) for MTAs.

Main Methods:

• Utilized nano-differential scanning fluorimetry (nanoDSF) for high-throughput screening of compounds.
• Validated the nanoDSF assay using the Prestwick Chemical Library (1520 approved compounds).
• Evaluated compound-tubulin interactions and their effects on tubulin polymerization dynamics.

Main Results:

• The nanoDSF assay successfully identified all known MTAs within the Prestwick Chemical Library.
• Discovered potential novel antitubulin agents among drugs approved for other medical conditions.
• Identified a novel structure-activity relationship within carbendazim and phenothiazine drug classes.

Conclusions:

• The developed nanoDSF assay offers a more efficient and informative method for MTA screening compared to existing assays.
• The study opens avenues for drug repositioning of newly identified MTAs for cancer therapy.
• Findings provide valuable insights for the rational design and optimization of novel MTA drug candidates with unique chemical scaffolds.