Abstract
10042 Background: Chimeric transcription factors are ideal anti-cancer targets since they are only present in tumor cells, however they are often considered ‘undruggable’ proteins. The EWS-FLI1 fusion protein of Ewings sarcoma (ES) has been validated as an anticancer target both alone and as a partner of RNA Helicase A (RHA). Our prior work identified (S)-YK-4-279 as an enantiospecific inhibitor of EWS-FLI1 by blocking the interaction with RHA leading to apoptosis. Methods: Pharmacokinetic (PK) models of YK-4-279 for both IP and IV administration were developed in SD rats and BL6 mice using drug concentrations determined by a validated LC-MS/MS assay. Xenograft ES mice validated PK models with apoptosis measured by TUNEL. A novel nude rat ES orthotopic xenograft was created give (S)-YK-4-279 by continuous IV infusion. Results: SD rat and BL6 mouse PK modeling demonstrated an elimination half-life t1/2 of 30 minutes following IV administration; SCID/bg mice demonstrated 50% faster clearance. A survival curve showed maximal killing of ES cells between 1 and 3 microM YK-4-279 over a 40-hour time course. Clonogenic replating assays demonstrated 3 microM exposure for 72 hours would reduce replating efficiency of ES cells to less than 0.01%. SCID/bg ES xenografts treated with IP YK-4-279 BID for 6 doses showed a 25-35% enantiospecific tumor regression with an average 3.5-fold increase in apoptosis. A nude rat xenograft, with continuous infusion (S)-YK-4-279 maintained an average level of 4.9 microM in plasma for 26 days. The ES1 xenograft tumor responded in 4 of 5 animals, with complete regression in 2 of 5, without toxicity. Conclusions: A combination of PK modeling and cell culture studies confirmed that (S)-YK-4-279 is required to be present at low microM levels for optimal tumor response. These levels were achieved in a novel rat xenograft of ES in order to demonstrate an important proof of efficacy. These PK-driven xenograft therapy studies are useful for development of PK models to compare YK-4-279 levels with functional activity. Targeting ‘undruggable’ protein-protein interactions with small molecules is novel and the ES model shows that continuous IV infusion may be required for optimal clinical translation.
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