• Science
Solute Carrier (SLC) Transporter Superfamily
Unexplored drug target that can bring hope to incurable diseases

SLC transporters unexplored
as a drug target

Survey of the drugs approved by the Food and Drug Administration indicates that 667 genes were targeted for drug discovery as of 2017.
The breakdown of the targets are as follows: 12%, 19%, 10%, 3%, and 56% for G protein-coupled receptors (GPCRs), ion channels, kinase, SLC transporters, and others, respectively.
Only 13 drugs targeting SLC transporters have been approved, and clinical development projects targeting new SLC transporters are in progress only for 10 drug candidates.

Why had SLC transporters been outside the targets
for drug discovery until recently?

As a matter of fact, over 400 transport proteins have been identified as members of the SLC transporter superfamily. Despite this, why is it that only a few drugs targeting SLC transporters have been developed so far?
This is because SLC transporters have multiple and diverse functions and complex molecular configurations, which mostly remained obscure until recent years.
Thanks to recent advances in science, however, a rapid progress is being made in understanding the functions of SLC transporters, particularly an amino acid transporter (e.g., LAT1/SLC7A5).1)2)

What is the amino acid transporter LAT1 (SLC7A5),
a recent attention-getting drug target?

Transporters mediate a variety of biologically essential responses and take necessary nutrients into cells. More than 50 amino acid transporters have been identified to date. When cells turn cancerous or start to grow rapidly, LAT1 (SLC7A5) expression on the cell membrane is enhanced, leading to increased uptake of amino acids and explosive cell proliferation. On the other hand, LAT2 is expressed on normal cells and takes in amino acids more slowly than LAT1 (SLC7A5) does, thus contributing to slow cell division. Focusing attention on this difference, J-Pharma developed JPH203, a low molecular weight compound that selectively inhibits LAT1 (SLC7A5). As shown in the following figures, JPH203 inhibits LAT1 (SLC7A5)-mediated uptake of amino acids in cancer cells, thereby driving them to cell death, whereas it does not inhibit LAT2 expressed on normal cells. J-Pharma is proceeding with clinical trials of JPH203 for biliary tract cancer, a disease in need of more effective treatments, with the aim of developing an anticancer drug with fewer side effects.
In addition, J-Pharma introduced OKY-034, another LAT1 (SLC7A5) inhibitor whose structure is different from that of JPH203, from Osaka University, and a clinical trial of this inhibitor for pancreatic cancer is under way.
Scientific research on LAT1 (SLC7A5) has lately progressed, and its molecular structure has just been defined.1) 2)
LAT1 has been found to be expressed not only on cancer cells but also on highly proliferative cells such as immunocytes. Importantly, numerous reports have recently published on the key role that LAT1 plays in autoimmune diseases including rheumatoid arthritis,3)type 1 diabetes mellitus,4)and multiple sclerosis.5)J-Pharma is exploring the application of the LAT1 inhibitor to such autoimmune diseases as the next target.

1) Nat Struct Mol Biol. 2019;26:510–7.
2) Nature 2019; 568:127-130.
3) Front Immunol. 2018;9:53
4) J Physiol 2007;581(Pt 3):1323-32
5) WO2020072608A1

SLC transporters

Draft illustration (LAT1 [SLC7A5] inhibition)

J-Pharma, the discoverer of amino acid transporter LAT1 (SLC7A5)

Amino acid transporter LAT1 (SLC7A5) has lately started to come under the spotlight as a target for drug discovery. In fact, this transporter was discovered by Hitoshi Endou, MD, Ph.D,1)the founder of J-Pharma. As a pioneering researcher of transporters, he worked for many years together with Prof. Kanai,2)Graduate School of Medicine, Osaka University, and discovered 13 new transporters3)that play an important role in living organisms, besides LAT1/SLC7A5.
J-Pharma is working on clinical development projects for two new drug candidates with a completely different structural formula from each other that target LAT1 (SLC7A5).
J-Pharma’s current position as a front-runner in the new drug development targeting LAT1 (SLC7A5) is supported by the deep science of transporters nurtured through long-term collaborative research by Dr. Endou and Prof. Kanai.

1) Former associate professor at Faculty of Medicine the University of Tokyo, current professor at Kyorin University
2) Prof. Kanai currently serves as chairman of the science advisory board of J-Pharma.
3) The discovered transporters include amino acid transporters (e.g., LAT1, human LAT2, LAT3, ASCT2, and TAT1) as well as glucose transporters and uric acid transporters (e.g., SGLT2, OAT1, OAT2, OAT3, OAT4, CT2, and URAT1). Some new drugs targeting SGLT2 and URAT1 molecules have already been created. In particular, the new drug targeting SGLT2 was such an innovative antidiabetic that Prof. Kanai was awarded the Prime Minister Prize in 2019 for the identification of SGLT2 and the development of its inhibitor.

From an academia-originated venture
into a Japan-originated global biopharmaceutical company

Originated from the world’s most advanced academic research by Dr. Endou and Prof. Kanai, J-Pharma is now on the verge of making a significant leap forward. The assumption of the presidency of J-Pharma in December 2018 by Masuhiro Yoshitake, who gained abundant experience for years in research and development, business development, and sales strategies as a member of the executive team in a leading drug company in Japan, triggered the acceleration of pipeline and business development. In April 2019, J-Pharma concluded a licensing contract with Ohara Pharmaceutical Co., Ltd., for joint development in Japan and certain countries of Asia and Africa. (The development right in Europe and the US is retained by J-Pharma.) J-Pharma subsequently discovered a companion diagnostic that helps stratify appropriate patients for treatment with JPH203. J-Pharma also entered on elaborate feasibility forecasting and budget control, which efforts have contributed to a steady financing. J-Pharma is determined to branch out into the US and other countries and advance the development of new medicines with the goal of becoming one of Japan’s leading biopharmaceutical company.

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