Overexpression of energy dependant drug efflux pumps in cancers has been shown to be correlated with multi-drug resistance. This is a serious issue as patients who develop refractory cancers have average five year survival rates as low as 10-30%. Administration of drug efflux pump inhibitors has been explored to resensitize multi-drug resistant (MDR) cancers to chemotherapy drugs. Many inhibitions however were toxic at levels required for effective pump inhibition and showed many off-target side effects. Selective delivery of these inhibitors via receptor mediated endocytosis provides an attractive strategy to selectively resensitize MDR cancers while minimizing toxicity and side effects. Two amino acid receptors, LAT1 and Asct2, are overexpressed in many cancers which also commonly develop multi-drug resistance. Selective delivery of the latest generation pump inhibitors may be achieved via conjugation to LAT1 or Asct2 recognition elements. MDR cancer cell lines will be used to guide and optimize the LAT1/Asct2 recognition element and conjugation site. Inhibition of the conjugated sensitizer will be compared to the parent compound and the role of the vector in delivery of the conjugate will be determined by blocking LAT1/Asct2 receptors. Potency, efficacy, selectivity, toxicity, and off-target effects will be explored though DMPK analysis and orthotopic xenograft models.
The most common reason for the development of resistance of cancers to multiple classes of anticancer drugs is through the over-expression of efflux pumps. Targeted inhibition of these pumps could resensitize the cancer to chemotherapy drugs while minimizing side effects.
|Tsai, Andy S; Chen, Ming; Roush, William R (2013) Chiral Bronsted acid catalyzed enantioselective synthesis of anti-homopropargyl alcohols via kinetic resolution-aldehyde allenylboration using racemic allenylboronates. Org Lett 15:1568-71|