"Brain cancer" potential target LAT1 has clear drug design ideas

Brain cancer, due to the particularity of the tumor site, the natural barrier of the BBB system, is still one of the most evil cancers
.
For brain cancer, although drugs have been approved for the market, no breakthrough therapeutic drugs have been born.
Therefore, the search for "targets & mechanisms of action & drugs" with great potential has never stopped, and clinical trials are often "external".
One of the topics
.
Today, I will introduce you to LAT1, a potential target in the field of brain cancer.
Although its clear mechanism of action makes drug design clear, it also has technical characteristics that are difficult to break through
.
01LAT1 target introduction LAT (L-type amino transporters), that is, L-type amino acid transporters, the main function is the transport of neutral amino acids including essential amino acids.
The subtypes are LAT1, LAT2, LAT3, LAT4 in order of time discovery, among which LAT1 The research is relatively the most
.
LAT1: Structurally, there are 512 amino acids, which are mainly expressed on the surface of the cell membrane; functionally, it needs to be covalently combined with the protein CD98, which penetrates the cell membrane for a single time, through disulfide bonds to perform its function of transporting amino acids.
Therefore, CD98 is considered to be Functional protein of LAT; in terms of distribution, human LAT1 is expressed in many tissues of the human body, but it is only highly expressed in a few tissues such as the brain, breast, lung, testis, uterus, ovary, placenta and retina, and in other normal tissues of adults Is rarely detected
.
At present, it is believed that the existence of LAT1 is related to the uptake and reabsorption of amino acids by tumor cells.
Overexpression of LAT1 plays an important role in the continuous proliferation of malignant tumor cells.
It is closely related to tumor staging, tumor tissue angiogenesis and tumor patient prognosis
.
02LAT1 features in the BBB system BBB acts as a barrier structure for the exchange of substances between the CNS and the blood.
It actively takes in the nutrients needed by the CNS and excretes or blocks the entry of substances that damage the CNS to ensure the physiological stability of the CNS
.
This barrier function of BBB also prevents most of the "brain treatment" drugs from entering the brain tissue, which seriously affects the treatment of CNS diseases
.
How to transport drugs "into the brain" and enrich them in brain tissue to exert their drug effects has become a hot and difficult point that encephalopathy scholars have paid attention to in recent years
.
As mentioned above, LAT1 plays an important role in the BBB and can promote the entry of nutrients and drugs into the CNS.
These drugs that can enter the CNS have been found to have a high degree of structural similarity with the endogenous substrates of LAT1, which can be transported by LAT1 after degradation and modification.
Into the brain
.
For example, the anti-epileptic drug gabapentin can be transported into the CNS through it
.
In addition, it is also found to be highly upregulated in cancer, which is characterized by a strong demand for amino acids for growth and proliferation
.
Therefore, among all influx transporters, LAT1 is a very ideal brain-targeted drug delivery carrier.
Therefore, LAT1 is considered an important drug target for cancer treatment
.
03 The substrate of the drug LAT1 transported by LAT1 needs to contain both a positively charged amino group and a negatively charged carboxyl group, as well as a hydrophobic or aromatic structure next to the central hydrogen bond acceptor.
Therefore, amino acid analogs are undoubtedly the most ideal for LAT1 The transport substrate
.
For example, levodopa, thyroid hormones (T3 and T4), melphalan, baclofen, and gabapentin, which were marketed in the early years, have a certain transport capacity (Vmax≈40-60nmol/min/g) and binding through the blood-brain barrier.
Affinity (Km≈10-200μM)
.
Another study also found that carboxylic acid esters and hydroxamic acid derivatives of amino acid analogs are also the preferred substrates of LAT1
.
By calculation, the related physical and chemical properties of LAT1 and LAT2 and the substrate are shown in the figure below.
These factors include pKa, logP, logDpH7.
4, polar surface area (PSA) and the number of hydrogen bond donor groups (HBD)
.
Through the analysis of the figure below, although the LAT substrate shows diversity in its physical and chemical parameters (such as logDpH7.
4), the core information is that the structure must be similar to amino acids.
Due to this extremely harsh structural restriction, there are currently only Up to 10 clinically used drugs are substrates of LAT1 or LAT2
.
For example, melphalan, a nitrogen mustard derivative of the neutral amino acid l-phenylalanine, is an antitumor drug for the treatment of multiple myeloma, breast cancer, and ovarian cancer
.
According to the research, melphalan shows a Km value of 150μM for LAT transporter in the rat BBB; however, although melphalan is transported by LAT1, its affinity for the carrier is not high, and it is derived from the large endogenous structure.
Significant competition for sex amino acids
.
Therefore, standard dose administration to patients may not reach therapeutic concentrations in the brain
.
For another example, baclofen and gabapentin, which are structural analogs of GABA, can be transported through BBB for the treatment of epilepsy and postherpetic neuralgia
.
In the in vitro BBB model, baclofen can be transported by a neutral amino acid carrier; however, there is no report on the LAT1 transport system in in vivo studies
.
Gabapentin is an analogue of baclofen, which also confirmed the transport characteristics of BBB in in vivo experiments, but there is currently no experiment to further confirm the specific role of LAT1 in the transport process
.
04Global Research Drugs-The highest phase II drug varieties designed and developed for the target of LAT1, the world's highest phase is clinical phase II, the varieties are R-OKY-034F, TX-101, JPH-203; clinical I The variety of the period is NBQ72S
.
R-OKY-034F is a small molecule LAT1 inhibitor developed by Osaka University and Japan Agency For Medical Research And Development.
Its clinical indications are mainly pancreatic cancer; TX-101, developed by Telix Pharmaceuticals, is mainly developed clinically as a diagnostic reagent Use; JPH-203, the development company is J-Pharma, the main clinical indication is cholangiocarcinoma; NBQ72S, the development company is Quadriga BioSciences, the main clinical indication is brain cancer
.
PS: The reported compound structures corresponding to the above drugs are all amino acid analogs
.
05 Another design idea-prodrugs By using the prodrug method, drug molecules can be converted into substrates that mimic amino acids, so that it is possible to use LAT1 to mediate and selectively deliver to target cells, thereby passing through the BBB
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For example, aspartic acid-modified doxorubicin (Asp-DOX) can actively target HepG-2 cells (a human liver cancer cell line that highly expresses LAT1), and this targeting property can further promote The uptake of AspDOX by cancer cells is improved
.
In addition, LAT1 is also used to promote the accumulation of efflux transporter inhibitors and maintain a continuous high concentration of cytotoxic drugs
.
Such as Probenecid (PRB, an efflux inhibitor), as one of the prodrugs using LAT1, interacts with multi-resistance protein (MRP), P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) It can increase cell accumulation of vinblastine and its anti-proliferative effect
.
In addition, several prodrugs based on LAT1 have been designed to improve the metabolic stability of the drug
.
For example, gemcitabine-threonine amide prodrugs not only show higher anticancer effects in vitro, but also have better pharmacokinetic characteristics than gemcitabine, and have certain potential for the treatment of pancreatic cancer
.
06 Summary The above is the current research status of the target LAT1
.
Although no milestones have occurred yet, its clear mechanism of action has laid the material foundation for the targeted release of drugs
.
However, how to develop better drug molecules requires medicinal chemists with more basic molecular design capabilities and sophisticated drug development
.
At the same time, the druggability of the target needs to be further determined by researchers, especially as the basic research information for the direction of brain cancer, and in-depth mechanism verification is needed.

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The development of brain cancer drugs is significantly more difficult than other cancers.
Therefore, potential targets similar to LAT1 need to be cherished and studied! References: 1.
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