Developing selective L-Amino Acid Transport 1 (LAT1) inhibitors: A Structure-Activity Relationship overview
Main Article Content
Abstract
System L amino acid transporters are a member of the Solute Carrier transporter Family (SLC). L-Amino acid transporter 1 (LAT1) belong to SLC7 and requires the heavy chained 4F2hc chaperone protein for amino acid transport. LAT1 is expressed in tumor cells and cancerous cells in vivo are strongly linked to LAT1 expression. Herein, we provide historical aspects regarding initial Structure Activity Relationship (SAR) findings reported in 2002 with the oocyte model and in 2008 with S2-LAT1 and S2-LAT2 cell lines. We summarize a series of dichloro- dibromo- and diiodo- tyrosine analogs that were prepared, and tested their potential to inhibit leucine transport in vitro to afford IC50 values with a few being low microM LAT1 inhibitors. We then summarize our efforts regarding novel LAT1 inhibitors with sub-nanomolar (nM) IC50s to produce JPH203 which has completed Phase I clinical trial and is currently in Phase II trial in Japan. We describe differences observed between LAT1 and LAT2. Overall, we provide an expanded SAR model regarding potent and selective LAT1 inhibitors.
Article Details
How to Cite
WEMPE, Michael F. et al.
Developing selective L-Amino Acid Transport 1 (LAT1) inhibitors: A Structure-Activity Relationship overview.
Medical Research Archives, [S.l.], v. 7, n. 12, dec. 2019.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2014>. Date accessed: 22 nov. 2024.
doi: https://doi.org/10.18103/mra.v7i12.2014.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Kanai, Y., Segawa, H., Miyamoto, K., Uchino, H., Takeda, E., Endou, H., 1998. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J. Biol. Chem. 273, 23629-23632.
2. Segawa, H., Fukasawa, Y., Miyamoto, K., Takeda, E., Endou, H., Kanai, Y., 1999. Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J. Biol. Chem. 274, 19745-19751.
3. Babu, E., Kanai, Y., Chairoungdua, A., Kim, D.K., Iribe, Y., Tangtrongsup, S., Jutabha, P., Li, Y., Ahmend, N., Sakamoto, S., Anzai, N., Nagamori, S., Endou, H., 2003. Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J. Biol. Chem. 278, 43838-43845.
4. Bodoy, S., Martin, L., Zorzano, A., Palacin, M., Estevez, R., Bertran, J., 2005. Identification of LAT4, a novel amino acid transporter with system L activity. J. Biol. Chem. 280, 12002-12011.
5. Fukasawa, Y., Segawa, H., Kim, J.Y,, Charoungdua, A., Kim, D.K., Endou, H., Endou, Y., 2000. Identification and characterization of a Na+-independent neutral amino acid transporter which associates with the 4F2 heavy chain and exhibits selectivity for small neutral D- and L-amino acids. J. Biol. Chem. 275, 9690-9698.
6. Yanagida, O., Kanai, Y., Chairoungdua, A., Kim, D.K., Segawa, H., Nii, T., Cha, S.H., Matsuo, H., Fukushima, J., Fukasawa, Y., Tani, Y., Taketani, Y., Uchino, H., Kim, J.Y., Inatomi, J., Okayasu, I., Miyamoto, K., Takeda, E., Goya, T., Endou, H., 2001. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim. Biophys. Acta. 1514, 291-302.
7. Ohkame, H., Masuda, H., Ishii, Y., Kanai, Y., 2001. Expression of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in liver tumor lesions of rat models. J. Surg. Oncol. 78, 265-271.
8. Kobayashi, H., Ishii, Y., Takayama, T., 2005. Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. J. Surg. Oncol. 90, 233-238.
9. Nakanishi, K., Matsuo, H., Kanai, Y., Endou, H., Hiroi, S., Tominaga, S., Mukai, M., Ikeda, E., Ozeki, Y., Aida, S., Kawai, T., 2006. LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Virchows Arch. 448, 142-150.
10. Nawashiro, H., Otani, N., Shinomiya, N., Fukui, S., Ooigawa, H., Shima, K., Matsuo, H., Kanai, Y., Endou, H., 2006. L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Int. J. Cancer. 119, 484-492.
11. Kaira, K., Oriuchi, N., Otani, Y., Shimizu, K., Tanaka, S., Imai, H., Yanagitani, N., Sunaga, N., Hisada, T., Ishizuka, T., Dobashi, K., Kanai, Y., Endou, H., Nakajima, T., Endo, K., Mori, M., 2007. Fluorine-18-alpha-methyltyrosine positron emission tomography for diagnosis and staging of lung cancer: a clinicopathologic study. 13, 6369-6378.
12. Sakata, T., Ferdous, G., Tsuruta, T., Satoh, T., Baba, S., Muto, T., Ueno, A., Kanai, Y., Endou, H., Okayasu, T., 2009. L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Path. Int. 59, 7-18.
13. Uchino, H., Kanai, Y., Kim, D.K., Wempe, M.F., Chairoungdua, A., Morimoto, E., Anders, M.W., Endou, H., 2002. Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition. Mol. Pharmacol. 61, 729-737.
14. Morimoto, E., Kanai, Y., Kim, do. K., Chairoungdua, A., Choi, H.W., Wempe, M.F., Anzai, N., Endou, H., 2008. Establishment and characterization of mammalian cell lines stably expressing human L-type amino acid transporters. J. Pharmacol. Sci. 108, 505-516.
15. Eswar N, Eramian D, Webb B, Shen MY, Sali A. Protein structure modeling with MODELLER. Methods Mol Biol. 2008; 426:145-59.
16. Gao X, Zhou L, Jiao X, Lu F, Yan C, Zeng X, Wang J, Shi Y. Mechanism of substrate recognition and transport by an amino acid antiporter. Nature 2010 463(7282):828-32.
17. Fletcher, R, Reeves, CM. Function Minimization by Conjugate Gradients. Comput. J. 1964, 7, 149-154.
18. Feig M, Onufriev A, Lee MS, Im W, Case DA, Brooks CL. Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures. J Comput Chem 2004; 25:265-284.
19. Koska J, Spassov VZ, Maynard AJ, Yan L, Austin N, Flook PK and Venkatachalam CM. Fully automated molecular mechanics based induced fit protein-ligand docking method. J Chem Inf Model 2008, 48(10): 1965-1973.
20. Tirado-Rives J and Jorgensen WL. Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding. J Med Chem 2006, 49, 5880-5884.
21. Vallabhajosula, S., 2007. 18F-labeled positron emission tomographic radiopharmaceuticals in oncology: an overview of radiochemistry and mechanisms of tumor localization. Semin. Nucl. Med. 37, 400-419.
22. Endou, H., Kanai, Y., Tsujihara, K., Saito, K., 2008. Aromatic Amino Acid Derivatives and Medicinal Compositions. US Patent 7,345,068 B2.
23. Wempe, M.F., Endou, H. 2011. Alpha-substituted and alpha-unsubstituted aromatic amino acid derivatives and compositions thereof for use to treat, diagnose, or monitor a medical considition. US Patent Application 20110150767.
24. Oda, K., Hosoda, N., Endo, H., Saito, K., Tsujihara, K., Yamamura, M., Sakata, T., Anzai, N., Wempe, M.F., Kanai, Y., Endou, H., 2010. L-type Amino Acid Transporter 1 Inhibitors Inhibit Tumor Cell Growth. Cancer Science, 101, 173-179.
25. Wempe, M.F., Rice, P.J., Lightner, J.W., Jutabha, P., Hayashi, M., Anzai, N., Wakui, S., Kusuhara H., Sugiyama, Y., Endou, Y., 2012. Metabolism and pharmacokinetic studies of JPH203, an L-amino acid transporter 1 (LAT1) selective compound. Drug Metab. Pharmacokinet. 27, 1, 155-161.
2. Segawa, H., Fukasawa, Y., Miyamoto, K., Takeda, E., Endou, H., Kanai, Y., 1999. Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J. Biol. Chem. 274, 19745-19751.
3. Babu, E., Kanai, Y., Chairoungdua, A., Kim, D.K., Iribe, Y., Tangtrongsup, S., Jutabha, P., Li, Y., Ahmend, N., Sakamoto, S., Anzai, N., Nagamori, S., Endou, H., 2003. Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J. Biol. Chem. 278, 43838-43845.
4. Bodoy, S., Martin, L., Zorzano, A., Palacin, M., Estevez, R., Bertran, J., 2005. Identification of LAT4, a novel amino acid transporter with system L activity. J. Biol. Chem. 280, 12002-12011.
5. Fukasawa, Y., Segawa, H., Kim, J.Y,, Charoungdua, A., Kim, D.K., Endou, H., Endou, Y., 2000. Identification and characterization of a Na+-independent neutral amino acid transporter which associates with the 4F2 heavy chain and exhibits selectivity for small neutral D- and L-amino acids. J. Biol. Chem. 275, 9690-9698.
6. Yanagida, O., Kanai, Y., Chairoungdua, A., Kim, D.K., Segawa, H., Nii, T., Cha, S.H., Matsuo, H., Fukushima, J., Fukasawa, Y., Tani, Y., Taketani, Y., Uchino, H., Kim, J.Y., Inatomi, J., Okayasu, I., Miyamoto, K., Takeda, E., Goya, T., Endou, H., 2001. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim. Biophys. Acta. 1514, 291-302.
7. Ohkame, H., Masuda, H., Ishii, Y., Kanai, Y., 2001. Expression of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in liver tumor lesions of rat models. J. Surg. Oncol. 78, 265-271.
8. Kobayashi, H., Ishii, Y., Takayama, T., 2005. Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. J. Surg. Oncol. 90, 233-238.
9. Nakanishi, K., Matsuo, H., Kanai, Y., Endou, H., Hiroi, S., Tominaga, S., Mukai, M., Ikeda, E., Ozeki, Y., Aida, S., Kawai, T., 2006. LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Virchows Arch. 448, 142-150.
10. Nawashiro, H., Otani, N., Shinomiya, N., Fukui, S., Ooigawa, H., Shima, K., Matsuo, H., Kanai, Y., Endou, H., 2006. L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Int. J. Cancer. 119, 484-492.
11. Kaira, K., Oriuchi, N., Otani, Y., Shimizu, K., Tanaka, S., Imai, H., Yanagitani, N., Sunaga, N., Hisada, T., Ishizuka, T., Dobashi, K., Kanai, Y., Endou, H., Nakajima, T., Endo, K., Mori, M., 2007. Fluorine-18-alpha-methyltyrosine positron emission tomography for diagnosis and staging of lung cancer: a clinicopathologic study. 13, 6369-6378.
12. Sakata, T., Ferdous, G., Tsuruta, T., Satoh, T., Baba, S., Muto, T., Ueno, A., Kanai, Y., Endou, H., Okayasu, T., 2009. L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Path. Int. 59, 7-18.
13. Uchino, H., Kanai, Y., Kim, D.K., Wempe, M.F., Chairoungdua, A., Morimoto, E., Anders, M.W., Endou, H., 2002. Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition. Mol. Pharmacol. 61, 729-737.
14. Morimoto, E., Kanai, Y., Kim, do. K., Chairoungdua, A., Choi, H.W., Wempe, M.F., Anzai, N., Endou, H., 2008. Establishment and characterization of mammalian cell lines stably expressing human L-type amino acid transporters. J. Pharmacol. Sci. 108, 505-516.
15. Eswar N, Eramian D, Webb B, Shen MY, Sali A. Protein structure modeling with MODELLER. Methods Mol Biol. 2008; 426:145-59.
16. Gao X, Zhou L, Jiao X, Lu F, Yan C, Zeng X, Wang J, Shi Y. Mechanism of substrate recognition and transport by an amino acid antiporter. Nature 2010 463(7282):828-32.
17. Fletcher, R, Reeves, CM. Function Minimization by Conjugate Gradients. Comput. J. 1964, 7, 149-154.
18. Feig M, Onufriev A, Lee MS, Im W, Case DA, Brooks CL. Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures. J Comput Chem 2004; 25:265-284.
19. Koska J, Spassov VZ, Maynard AJ, Yan L, Austin N, Flook PK and Venkatachalam CM. Fully automated molecular mechanics based induced fit protein-ligand docking method. J Chem Inf Model 2008, 48(10): 1965-1973.
20. Tirado-Rives J and Jorgensen WL. Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding. J Med Chem 2006, 49, 5880-5884.
21. Vallabhajosula, S., 2007. 18F-labeled positron emission tomographic radiopharmaceuticals in oncology: an overview of radiochemistry and mechanisms of tumor localization. Semin. Nucl. Med. 37, 400-419.
22. Endou, H., Kanai, Y., Tsujihara, K., Saito, K., 2008. Aromatic Amino Acid Derivatives and Medicinal Compositions. US Patent 7,345,068 B2.
23. Wempe, M.F., Endou, H. 2011. Alpha-substituted and alpha-unsubstituted aromatic amino acid derivatives and compositions thereof for use to treat, diagnose, or monitor a medical considition. US Patent Application 20110150767.
24. Oda, K., Hosoda, N., Endo, H., Saito, K., Tsujihara, K., Yamamura, M., Sakata, T., Anzai, N., Wempe, M.F., Kanai, Y., Endou, H., 2010. L-type Amino Acid Transporter 1 Inhibitors Inhibit Tumor Cell Growth. Cancer Science, 101, 173-179.
25. Wempe, M.F., Rice, P.J., Lightner, J.W., Jutabha, P., Hayashi, M., Anzai, N., Wakui, S., Kusuhara H., Sugiyama, Y., Endou, Y., 2012. Metabolism and pharmacokinetic studies of JPH203, an L-amino acid transporter 1 (LAT1) selective compound. Drug Metab. Pharmacokinet. 27, 1, 155-161.