JPH203 | LAT1 inhibitor

JPH203 (1597402-27-1) is a selective L-type amino acid transporter 1 inhibitor (LAT1 or SLC7A5; IC₅₀ = 140 nM for ¹⁴C-leucine uptake in S2-hLAT1 cells, and 60 nM for HT29 human colon adenocarcinoma cells: growth inhibition IC₅₀’s = 16.4 µM and 4.1 µM respectively for S2 and HT29  cells).¹ Also active in HT-29 mouse xenograft models.  JPH203 is active in a variety of cancer models and has progressed to clinical trials.² It sensitized A549 and MIA Paca-2 cells to radiation by enhancing cellular senescence via mTOR downregulation³ and sensitized EGFR-expressing cancer cell lines to gefitinib therapy⁴.  JPH203 treatment of non-small cell lung cancer cells led to downregulation of PD-L1 suggesting that LAT1 inhibition may help overcome the immune suppressive tumor microenvironment.⁵

References/Citations:

1. Oda et al. (2010) L-type amino acid transporter 1 inhibitors inhibit tumor cell growth; Cancer Sci. 101 173
2. Kanai (2022) Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics; Pharmacol. Ther. 230 107964
3. Bo et al. (2021) LAT1 inhibitor JPH203 sensitizes cancer cells to radiation by enhancing radiation-induced cellular senescence; Transl. Oncol. 14 101212
4. Saito et al. (2018), Amino acid starvation culture condition sensitizes EGFR-expressing cancer cell lines to gefitinib-mediated cytotoxicity by inducing atypical necroptosis; Int. J. Oncol. 52 1165
5. Liu et al. (2021), L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells; Int. J. Mol. Sci. 22 10955