Structural basis for the inhibition mechanism of LAT1-4F2hc complex by JPH203
Ziwei Hu, Renhong Yan
Abstract
The L-type amino acid transporter 1 (LAT1 or SLC7A5), coupled with 4F2hc (or SLC3A2), facilitates the transport of large neutral amino acids and thyroid hormones across cell membranes in a sodium-independent exchange manner 1 , 2 , 3 . LAT1 emerges as a significant anti-cancer target due to its role in suppressing the proliferation of various cancer cells when pharmacologically inhibited or knocked down/knocked out 4 , 5 , 6 , 7 . Its counterpart, LAT2, shares 54% sequence identity and 71% sequence similarity with LAT1 (Supplementary Fig. S1 ) and exhibits a broader substrate range, encompassing small amino acids, primarily found in normal tissues 6 , 8 , 9 . JPH203 (or KYT-0352), a triiodothyronine (T3)-derived amino acid, stands out for its ability to inhibit tumor growth in multiple cancer cell lines by selectively inhibiting LAT1’s transport activity rather than LAT2 10 . Currently, JPH203 is being evaluated in a Phase II clinical trial (UMIN000034080) for the treatment of biliary tract cancer. This follows a phase I clinical trial (UMIN000016546) that demonstrated the safety and efficacy of JPH203 11 . Despite advancements in understanding LAT1 and LAT2 structures 8 , 12 , 13 , 14 , 15 , the precise molecular mechanism underlying JPH203’s specific inhibition of the LAT1 – 4F2hc complex remains incompletely elucidated. In this study, we determined the cryo-EM structure of the LAT1 – 4F2hc complex bound with the JPH203 inhibitor, shedding light on the intricate details of its specific inhibition mechanism.