KOS-1584: a rationally designed epothilone D analog with improved potency and pharmacokinetic (PK) properties

Abstract

2535KOS-1584 (9,10 didehydroepothilone D) is a novel and potent analog of KOS-862 (epothilone D), an investigational anti-cancer compound currently being evaluated in Phase 2 and combination clinical trials. KOS-1584 was identified as part of a systematic effort to identify a new generation of epothilones that possess greater potency with improved pharmacological and pharmaceutical properties. KOS-1584 at 6 nM effectively induced tubulin polymerization in a cell-based assay using MCF-7, a breast cancer cell line, arresting the cells at G2/M phase of the cell cycle. Potent anti-proliferative activity against a broad range of tumor cell lines was observed in vitro, including hematologic and solid tumor cell lines, such as leukemia, breast, colon, lung, and ovary (average IC50 3.8 ± 1.4 nM, 3-12 times more potent compared to KOS-862 in the same experiment). The in vivo anti-cancer activity of KOS-1584 has been studied in several animal models: 1) human tumor cell hollow fiber models in nude mice using various cell lines (A549 lung adenocarcinoma, HT-29 colorectal carcinoma and SKOV3 ovarian adenocarcinoma); 2) MV522 human lung xenograft model in nude mice; and 3) HCT-116 human colorectal xenograft model in nude rats. KOS-1584 significantly inhibited the tumor cell growth in the hollow fiber models, and reduced the tumor size in MV522 xenograft model in mice and HCT-116 xenograft model in rats; antitumor effects were observed at 3-5 mg/kg, compared to 30 mg/kg with KOS-862. In addition, KOS-1584 was selected for development on the basis of its desirable PK properties: epothilones with antitumor effects in Phase 1-2 clinical trials have demonstrated excellent tissue penetration (volume of distribution Vd>500 L) and long elimination half-lives (t½ >40 hours). In the dog (the most predictive species for this class of compound), KOS-1584 showed a 3-fold increased Vd and 3-fold longer t½ compared to KOS-862. Allometric scaling, using the PK of KOS-1584 in the mouse, rat, dog and monkey, predicted significantly improved PK properties in human. In this model, dog PK data were fitted to a 3-compartment model to obtain relevant PK constants; these were then applied to simulate a human plasma profile for KOS-1584. Consistent with improved potency, severely toxic doses in the rat and dog were 3-16 fold lower comparing the two epothilones with identical schedules. KOS-1584 entered Phase 1 clinical testing in late 2004 using a cyclodextrin formulation.