V-9302

V-9302 hydrochloride is a competitive antagonist of transmembrane glutamine flux. V-9302 hydrochloride selectively and potently targets the amino acid transporter ASCT2 (SLC1A5) not ASCT1^[1].

V-9302 hydrochloride inhibits ASCT2-mediated glutamine uptake (IC₅₀=9.6 µM) in HEK-293 cells. V-9302 hydrochloride inhibits ASCT2-mediated glutamine uptake in human cells in a concentration-dependent fashion. Treatment of HCC1806 cells with V-9302 hydrochloride resulted in a significant decrease in downstream levels including phosphorylated (P)-S6 and a moderate decrease in P-ERK levels, similar to knockdown of ASCT2^[1].Pharmacological blockade of ASCT2 with V-9302 hydrochloride resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress^[1].The phosphorylation levels of the mTOR, S6K, and S6 proteins were reduced by treatment with 20 μM of V-9302 hydrochloride in SKOV3-TR cells, indicating that V-9302 hydrochloride effectively inhibited the mTORC1/S6K signaling pathway^[2]. As the glutamine transporter inhibitor ，V-9302 hydrochloride suppresses tumor growth and increases T lymphocyte activation in a model of TNBC^[5]

In vivo,steady-state plasma concentrations were achieved at 4 h post-administration with a half-life of approximately 6 h in healthy mice. Besides,using anhymic nude mice bearing HCT-116 or HT29 cell line xenografts, V-9302 hydrochloride prevented tumor growth. V-9302 hydrochloride led to significantly decreased expression of p-S6 in tumor tissue in both HCT-116 and HT29 xenografts. In addition to decreased p-S6 IHC staining, V-9302 hydrochloride treatment led to elevated levels of cleaved caspase 3^[1]. In vivo xenograft tumor model of MDA-MB-231 cells, tumor growth was inhibited by V-9302 hydrochloride alone, and further inhibited by combination of V-9302 hydrochloride with other inhabitor^[3].The combination of CB-839 and V-9302 hydrochloride elicits a strong growth inhibition in both SNU398 and MHCC97H xenograft models, while single-drug treatment showed modest anti-tumor effects^[4]. ASCT2 inhibitor V-9302 hydrochloride may has influence in Alanine uptake in MRI^[7]. Blockade of glutamine uptake using V9302 hydrochloride combined mTORC1/2 inhibitor AZD2014 blocking the interaction between HDAC3 and GS not only significantly delayed the tumor growth but also resulted in partial or even complete tumor regression ^[6]

References:
[1]. Schulte ML, Fu A, et,al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med. 2018 Feb;24(2):194-202. doi: 10.1038/nm.4464. Epub 2018 Jan 15. PMID: 29334372; PMCID: PMC5803339.
[2]. Kim G, Jang SK,et,al. Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway. Int J Mol Sci. 2022 Aug 6;23(15):8761. doi: 10.3390/ijms23158761. PMID: 35955892; PMCID: PMC9369036.
[3]. Zhou Q, Lin W, et,al.Neddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells. Nat Commun. 2022 May 31;13(1):3034. doi: 10.1038/s41467-022-30559-2. Erratum in: Nat Commun. 2022 Jun 14;13(1):3424. PMID: 35641493; PMCID: PMC9156729
[4]. Jin H, Wang S, et,al. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. Elife. 2020 Oct 5;9:e56749. doi: 10.7554/eLife.56749. PMID: 33016874; PMCID: PMC7535927.
[5]. Edwards DN, Ngwa VM, et,al. Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest. 2021 Feb 15;131(4):e140100. doi: 10.1172/JCI140100. PMID: 33320840; PMCID: PMC7880417.
[6]. Zhang HL, Chen P, et,al. Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation. Adv Sci (Weinh). 2022 Jul;9(20):e2103887. doi: 10.1002/advs.202103887. Epub 2022 Feb 20. PMID: 35187863; PMCID: PMC9284171.
[7]. Yang SH, Choi Y, et,al. MRI measurement of alanine uptake in a mouse xenograft model of U-87 MG glioblastoma. Magn Reson Imaging. 2022 Aug 24;93:189-194. doi: 10.1016/j.mri.2022.08.015. Epub ahead of print. PMID: 36029935.