Enhancing Cancer Therapy with BAL101553: A Soluble Prodrug of the Microtubule Disruptor BAL27862

The synthetic compound BAL27862 has been identified for its ability to trigger cancer cell death by disrupting microtubules. This compound can be administered both intravenously and orally, showing effectiveness against various human cancers, including those resistant to traditional treatments. To enhance its water solubility and improve its formulation, a new prodrug, BAL101553, has been created.

The solubility of the compounds was measured using high-performance liquid chromatography (HPLC) after preparing saturated solutions. The in vitro antiproliferative impact was evaluated through the Crystal Violet assay. The effect on microtubules was determined by immunoblotting or immunofluorescence for α-tubulin. Pharmacokinetic studies were carried out on mice with colon carcinoma, administering BAL27862 or BAL101553 weekly for a month, and measuring compound levels in plasma, brain, and tumors. The therapeutic effect was assessed in a non-small cell lung cancer (NSCLC) mouse model using weekly maximum tolerated doses.

BAL27862 has very low water solubility, while BAL101553's hydrochloride salt is much more soluble. In vitro, BAL101553 showed slightly higher IC50 values for antiproliferation compared to BAL27862, which is expected due to its conversion to the active drug within cells. The antiproliferative activity of BAL101553 was linked to effective microtubule depolymerization, resulting in a unique formation of microtubule asters in dividing cells. This is a distinctive feature of BAL27862 not seen with conventional microtubule-targeting drugs. In vivo, BAL101553 was successfully converted to BAL27862. After intravenous administration, equivalent concentrations of the drug were found in the brain and tumors as in plasma, with no accumulation over time. BAL101553 reached a higher maximum tolerated dose than BAL27862, resulting in slightly lower peak concentrations but higher overall exposure to the active drug. The prodrug BAL101553 was well tolerated and showed significant antitumor effects in mice, comparable to BAL27862.

In conclusion, BAL101553, with its high water solubility, allows for intravenous administration without the need for potentially harmful solubilizing agents. The compound's in vitro profile, positive pharmacokinetic properties, and proven efficacy in animal models suggest it warrants further investigation as a potential treatment for human cancers.