Abstract 1347: BAL101553: An optimized prodrug of the microtubule destabilizer BAL27862 with superior antitumor activity
Authors: Pohlmann Jens , Bachmann Felix , Schmitt-Hoffmann Anne , Gebhardt Klaus , Spickermann Jochen , Nuoffer Claude , Biringer Gérard , O'Reilly Terence , Pruschy Martin , Lane Heidi A. 
Published: June 2012

Abstract
Background: BAL27862 is a novel small molecule, inducing apoptosis in cancer cells through microtubule destabilization. A series of amino acid-derived BAL27862 prodrugs was evaluated for solubility and in vivo conversion into drug. The Lys-prodrug BAL101553 was further compared with BAL27862 in animal models of human cancer.
Methods: Kinetic solubility of compounds was determined by diluting DMSO stock solutions with aqueous buffer. Pharmacokinetics and prodrug conversion were evaluated in mice. In vivo efficacy was analyzed in colon carcinoma SW480 and patient-derived mammary MaCa4151 xenografts. MTD dosing was used in all cases, adapted for each mouse strain.
Results: All amino acid-derived prodrugs showed significantly increased aqueous solubility compared to BAL27862, most pronounced at pH 3. At pH 5 and 6.5, the dibasic Lys-prodrug BAL101553 proved to be the most soluble compound (&gt;200 μM). In vivo conversion rates differed significantly between the prodrugs. Highest exposure to the parent drug was obtained with the Lys, Ala and Gly derivatives, whereas the exposure achieved with other amino acid prodrugs (e.g. Phe, Asn, Ser, Trp) was more than twofold lower. Combining high solubility, good conversion and oral bioavailability, BAL101553 was selected for further evaluation. In tumor models, BAL27862 was rapidly distributed into SW480 tumors after i.v. administration of drug or BAL101553. Strikingly, BAL27862 was retained in tumor ∼1.5 times longer after BAL101553 (T1/2: 8.3h) vs. BAL27862 (T1/2: 5.4h) administration. In all models, a higher MTD was reached with the prodrug, related to ∼60% prodrug conversion in vivo. In MaCa4151 xenografts, twice-weekly i.v. administration of BAL101553 (17 mg/kg BAL27862 equivalents [BE]) elicited superior antitumor effects (final T/C=30%; p&lt;0.05 vs. controls) as compared to BAL27862 (10 mg/kg; T/C=66%). Once-weekly dosing of BAL101553 (14 mg/kg BE) and BAL27862 (8 mg/kg) in the SW480 model resulted in final T/C's of 34% and 49% (both p&lt;0.001), resp. Strikingly, fractionation of the same total weekly dose did not significantly affect outcome for either BAL101553 (3x per day once-weekly: T/C=40%; 3x per week: T/C=26%; both p&lt;0.001) or BAL27862 (3x per day once-weekly: T/C=54%; 3x per week: T/C=54%; p=0.001 and p=0.002, resp.), suggesting antitumor response is related to AUC. Again, indications of superior antitumor responses were observed with all prodrug schedules in this model.
Conclusions: BAL101553 has been identified as a highly soluble prodrug of BAL27862, which can be administered p.o. or i.v. in the absence of solubilizing excipients known to be associated with adverse side-effects. Its administration facilitates higher tumor exposure to the active agent, with more profound responses in some tumor models. These data, together with a flexible dosing potential, support profiling of BAL101553 in cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1347. doi:10.1158/1538-7445.AM2011-1347