The "magic drug" rapamycin "one arrow and three eagles" anti-tumor

The "magic drug" rapamycin "one arrow and three eagles" anti-tumor

The "magic drug" rapamycin "three eagles with one arrow" anti-tumor "magic drug" rapamycin "three eagles with one arrow" anti-tumor

Anti-aging, anti-tumor, and improving neurodegenerative diseases.
.
.
In addition to being used as a powerful immunosuppressant for renal transplantation and anti-rejection, in recent years, rapamycin has been regarded as a "magic drug" with "one drug, multiple effects" "
.

However, at present, the only known clear target of rapamycin is mTOR, and exploring more unknown targets is the key to making the "magic drug" play a more "magical" therapeutic effect
.

In a study published in "Cell Chemical Biology" on October 26, Zhang Yaoyang, a researcher at the Interdisciplinary Research Center of Biology and Chemistry at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and his collaborators opened up more mysteries of the "magic medicine"
.

They found that in addition to mTOR, rapamycin can also directly target the "un-druggable" STAT3 and affect another "un-druggable" c-Myc to inhibit tumor cell growth

In an interview with China Science Daily, Zhang Yaoyang said that the reason for the potential advantage of rapamycin in anti-cancer drugs may be that it can target multiple oncogenes at the same time, playing the role of "three birds with one stone".
, "Taking one drug may produce the effect of multi-drug combination
.

"

Photo courtesy of Zhang Yaoyang and some team members interviewees

Photo courtesy of Zhang Yaoyang and some team members interviewees

Why is the "magic drug" "God"

Why is the "magic drug" "God"

In 1975, scientists isolated rapamycin from the soil on Easter Island in Chile
.

This is a macrolide compound that was initially regarded as an antifungal drug, but was later found to have a potent immunosuppressive effect

In recent years, researchers have gradually discovered that rapamycin also has other therapeutic effects, such as anti-aging, anti-tumor, and improving neurodegenerative diseases
.

But at present, only mTOR is known and relatively clear protein target for the role of rapamycin in the body

"Since rapamycin has so many effects, the known target mTOR alone cannot explain all the pharmacological mechanisms.
There must be other unknown and important targets
.

" Zhang Yaoyang believes that the discovery of an unknown target of rapamycin is right.

In 2016, based on years of accumulation and interest in mass spectrometry proteomics and chemical biology research, Zhang Yaoyang's team started this research to explore the unknown target behind the "magic drug"
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To find the target, you must first search for all possible candidate targets
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To this end, the researchers designed a rapamycin probe alk-rapa with photocrosslinking activity, and used chemical proteomics methods to identify 213 high-confidence candidate target proteins of rapamycin

"These proteins play an important role in a variety of cell biological processes
.

" said Sun Le , the first author of the paper and a doctoral student at the Center for Interdisciplinary Research in Biology and Chemistry of the Chinese Academy of Sciences

Chinese Academy of Sciences Chinese Academy of Sciences Chinese Academy of Sciences

She told reporters that the core part of this research is the design of functional molecular probes that have both photoreactivity and "click chemistry" reactivity
.

This is because most drug molecules and protein targets are combined in a non-covalent form, which is unstable and difficult to capture in target discovery studies for complex samples
.

With this kind of photo-crosslinking activity probe, under ultraviolet light irradiation, rapamycin can be firmly anchored to the protein target it acts on via a covalent bond
.

Then using protein profiling technology, researchers can discover potential target proteins

Two new targets discovered

Two new targets discovered

To find the target target from the 213 candidate target proteins of rapamycin is a needle in a haystack
.

"This requires a certain amount of experience, and there is also a trace of luck
.
" Sun Le said
.

Soon after the research was carried out, STAT3, which is "unable to make medicine", attracted the attention of the team
.
"The main
reason is that it does not have suitable small molecule binding pockets.
It is extremely difficult to develop drugs.
There is no successful precedent to be approved for clinical use, " Zhang Yaoyang explained
.

STAT3 is a transcription factor highly expressed in tumors, which regulates the transcriptional expression of many oncogenes
.
He told reporters that theoretically, through drug screening and design, if there are drugs that can directly target STAT3 and inhibit its activity, it will be expected to become an effective way of tumor treatment
.

Unfortunately, the surface of the STAT3 protein structure is relatively smooth and lacks hydrophobic or specific pockets for binding small molecules, making drug development very difficult
.

With the hypothesis of STAT3, the researchers through a series of cell and molecular level functional research, combined with DARTS, MS, SPR, CETSA, molecular calculation simulation and other methods of biochemistry, analytical chemistry, computational biology, and finally verified Rapamycin can directly target STAT3 and regulate its transcriptional activity
.

In the next study, they found an "unexpected" surprise: another "undruggable" transcription factor c-Myc can also be inhibited by rapamycin
.

Sun Le told reporters that in the multidimensional omics data, they found that rapamycin treatment of cells is not enough to cause significant changes in the entire proteomics, but it has a huge impact on the dynamic synthesis of proteins
.

Transcription factors are a class of proteins that can regulate the expression of many downstream genes
.
She suspected that some upstream transcription factors might be affected by rapamycin
.

Following this conjecture, the research team designed some experiments and finally proved that rapamycin can indeed affect c-Myc
.

Will be further optimized

Will be further optimized

Sun Le told reporters that the biggest difficulty of this study is how to prove that rapamycin can directly regulate the function of STAT3 without relying on mTOR
.

At present, there is only one clearly known target of rapamycin, mTOR, and mTOR and STAT3 are still inextricably linked
.
Therefore, even though the research team has proven through a variety of methods that rapamycin can directly physically bind to the STAT3 protein and affect its function, it is not enough to explain that the drug's in vivo mechanism of action is through the direct regulation of STAT3 production
.

To this end, the researchers designed a series of control experiments, and finally proved that the function of rapamycin to regulate STAT3 can be independent of mTOR
.

In the tumor cell line xenograft model, the researchers also found that long-term treatment of mice with rapamycin can cause the expression of STAT3 and c-Myc to decrease, thereby inhibiting tumor growth in the body
.

"Rapamycin, as a drug approved for marketing, has been shown to target or affect these two traditionally considered'unable to drug' targets in this study.
It is used in the development of'old drugs and new drugs' and oncology drugs.
Significant potential meaning and value
.
" Zhang Yaoyang said
.

In fact, while this research is being carried out, it is also facing fierce peer competition
.
Zhang Yaoyang believes that the results of the research are that on the one hand, the important target STAT3 was selected from many candidate proteins.
On the other hand, it has been accumulated by the team for many years, and the close cooperation between the research groups and the support of the research platform have an important relationship
.

Zhang Yaoyang said that the current use of rapamycin for tumor treatment is still in the initial stage of clinical research
.
"STAT3 is abnormally activated in a variety of tumors.
Our work has proved that rapamycin directly binds to inhibit STAT3 and affects the activity of c-Myc
.
In principle, it targets a variety of tumors with overexpression of STAT3, c-Myc and mTOR.
, Rapamycin may have inhibitory effects, but specific clinical indications require more clinical research and data
.
"

In Sun Le's view, the binding constant of rapamycin and STAT3 is at the submicromolar level, and the binding force is not strong
.
Therefore, in order to achieve the high efficiency and safety of small molecules in vivo, it is necessary to optimize and modify the structure of small molecules to improve the affinity of small molecules and proteins, and provide a new perspective for the drug development of STAT3 inhibitors
.

"In addition to STAT3 and c-Myc, we also found some other interesting and important protein targets among the candidate targets of rapamycin, which will be used in subsequent mechanism research and drug development
.
" Zhang Yaoyang said
.
(Source: Tian Ruiying, China Science News)

Related paper information: https://doi.
org/10.
1016/j.
chembiol.
2021.
10.
006

https://doi.
org/10.
1016/j.
chembiol.
2021.
10.
006