An Oncological Profile of Sagopilone (DB12391): From Rational Design to Clinical Discontinuation

1.0 Executive Summary

Sagopilone (DB12391), also known as ZK-EPO, represents a significant case study in modern oncology drug development. It emerged from an extensive lead optimization program as a third-generation, fully synthetic analogue of the natural product epothilone B. The compound was rationally designed by Bayer Schering Pharma AG to address the primary clinical limitations of the taxane class of chemotherapeutics, namely acquired drug resistance mediated by the P-glycoprotein (P-gp) efflux pump and the inability to treat central nervous system (CNS) malignancies.

Preclinically, Sagopilone exhibited a near-ideal pharmacological profile for a microtubule-stabilizing agent. It demonstrated potent, sub-nanomolar antiproliferative activity across a broad spectrum of human tumor models, including those with established resistance to paclitaxel. Crucially, it was confirmed not to be a substrate for P-gp, providing a clear mechanistic basis for its activity in multidrug-resistant (MDR) tumors. Furthermore, Sagopilone displayed the unique and highly sought-after ability to freely cross the blood-brain barrier (BBB), leading to significant antitumor efficacy in orthotopic models of glioblastoma and CNS metastases where standard agents like paclitaxel were ineffective. This combination of potent cytotoxicity, resistance evasion, and CNS penetration created exceptionally high expectations for its clinical translation.