Development of LAT‐1 inhibitors for the treatment of pancreatic cancers

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and represents one of the world's most deadly cancers with a five year survival of only 8%. As such there is a desperate need to develop effective new medicines for pancreatic cancers. The large neutral aminoacid transporter 1 (LAT‐1) is highly expressed in PDAC tumors and provides a conduit for these tumors to acquire essential amino acids like leucine and methionine. Beyond their incorporation into proteins, leucine is an important regulator of mTOR signaling and methionine is essential for one carbon metabolism and polyamine biosynthesis. Targeting LAT‐1 inhibits the uptake of these essential building blocks and inhibits cell growth.There has been significant interest in developing LAT‐1 inhibitors for oncology applications and virtually all of the known LAT‐1 inhibitors are predicated upon a phenylalanine scaffold. Here, we showed that piperazine‐based materials effectively inhibited leucine and methionine import into L3.6pl human pancreatic cancer cells. We also demonstrated that our lead LAT‐1 inhibitor resulted in a dose‐dependent decrease in intracellular methionine, leucine, and depleted polyamine pools in L3.6pl cells in vitro. Moreover, these treated cells were not rescued by exogenous polyamines indicating that polyamine import could not revive the treated cells. Our different molecular design provides new opportunities for enhanced targeting and both the synthesis and bioevaluation of these new LAT‐1 inhibitor designs will be discussed.Support or Funding InformationUCF College of Medicine (#25014202)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.