Abstract 4644: Efficacy, pharmacokinetics and tissue distribution of celastrol analogues SBI 064601, SBI 0640599 and SBI 0069272 in C.B-17 SCID mice bearing Daudi Burkitt's lymphoma xenografts

Abstract

Abstract Introduction: c-Myc plays an important role in cellular proliferation, differentiation, apoptosis and cell cycle progression and its overexpression is associated with aggressiveness and poor prognosis in many cancers. Three celastrol analogues, SBI 064601(601), SBI 0640599(599) and SBI 0069272(272) are potent c-Myc inhibitors. We have evaluated the ability of these celastrol analogues to inhibit Daudi lymphoma cells in vitro and in vivo and characterized the pharmacokinetics of these celastrol analogues in C.B-17 SCID mice bearing Daudi xenografts. Methods: Inhibition of Daudi cell growth by three celastrol analogues was assessed by MTT assay after 72 h of incubation. For the efficacy study, the mice bearing Daudi xenografts were treated with 20 mg/kg iv of 601, 599, 272 qdx5, or with 50 mg/kg of 601(iv) and 272 (iv and po), respectively on a qdx5 for two weeks schedule. For pharmacokinetic studies, the mice were administered all three analogues iv at 20 mg/kg and 272 was also given at 50 mg/kg iv and po. Plasma and tissues were collected between 5 and 1440 min. Concentrations of the analogues were determined by LC-MS/MS and non-compartmental analysis was performed using PK solutions. Results: The IC50's of 601, 599 and 272 against Daudi cells in vitro were 2.9 µM, 25.4 µM and 10.6 µM, respectively. The mean tumor time to two doublings for 601, 599 or 272 at 20 mg/kg iv were 16.5±0.9 , 12.7±3.3 and 14.5±3.8 days, respectively, compared with control (11.7±3.9 days). At 50 mg/kg, the mean tumor time to two doublings for 601(iv), or 272 (iv or po) were 10.7±6.0, 6.7±2.6 and 5.3±1.6 days, respectively, compared with control (7.1±2.9 days). Following a single iv dose with 20 mg/kg of the analogues or 50 mg/kg of 272, plasma and tumor Cmax occurred at 5 min. Plasma and tumor Cmax occurred at 30 min for 272 po. AUC0-t for 601, 599 and 272 at 20 mg/kg iv were 1219, 5417, and 9411 µg•min/ml, respectively. AUC0-t for 272 at 50 mg/kg iv and po were 21908 and 7184 µg•min/ml, respectively. Plasma t1/2 of 601, 599 and 272 at 20 mg/kg iv were approximately 165, 38, and 454 min respectively. Plasma t1/2 of 272 at 50 mg/kg iv or po were 763 and 239 min, respectively. Clearances for 601, 599 at 20 mg/kg iv and 272 at 50 mg/kg iv or po in plasma were 15.3, 3.7, 2.1, 2.5 and 7.0 ml/min/kg, respectively. Conclusion: 601 had the lowest IC50 against Daudi cells in vitro and resulted in a significant delay in tumor time to two doublings after 20 mg/kg iv. There were no significant effects of the other celastrol analogues on Daudi lymphoma growth in vivo at 20 mg/kg and 50 mg/kg iv or po. 601 is under further preclinical evaluation against other human tumor xenografts. Support: R01-CA078039 and P30-CA47904 Citation Format: Jianxia Guo, Kathleen Paul, Edward V. Prochownik, Nicholas Cosford, Robert A. Parise, Jan H. Beumer, Julie L. Eiseman. Efficacy, pharmacokinetics and tissue distribution of celastrol analogues SBI 064601, SBI 0640599 and SBI 0069272 in C.B-17 SCID mice bearing Daudi Burkitt's lymphoma xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4644. doi:10.1158/1538-7445.AM2014-4644