Cell Chemical Biology: "Miracle Drug" Rapamycin, "One Arrow and Three Eagles" Anti-tumor

Rapamycin (Rapamycin), a macrolide compound, was first isolated from Streptomyces in the soil of Easter Island and was found to have antifungal effects, and was later found to have immunosuppressive functions
.

It was approved by the FDA in 1999 as an immunosuppressant to reduce the anti-rejection reaction after kidney transplantation

In recent years, the role of rapamycin in anti-tumor, anti-aging and improvement of neurodegenerative diseases has been continuously reported, and it is called the "magic drug"
.

Obviously, mTOR, a known target of rapamycin, cannot explain all its pharmacological mechanisms.

Recently, Zhang Yaoyang's research group from the Interdisciplinary Research Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , published a research paper titled: Rapamycin targets STAT3 and impacts c-Myc to suppress tumor growth in Cell Chemical Biology
.

Cell Chemical Biology

The study found that in addition to inhibiting the known target of mTOR, rapamycin can also directly target the "un-druggable" STAT3 and affect another "un-druggable" c-Myc.
The effect of "three eagles"
.

The research first designed a rapamycin probe alk-rapa with photocrosslinking activity and "click chemistry" activity through chemical proteomics methods, and identified 213 high-confidence candidate target proteins of rapamycin
.

These proteins play an important role in a variety of cell biology processes

The research has verified that rapamycin can be directly combined with STAT3 through a series of functional studies at the cellular and molecular level, and using various biochemical, analytical chemistry, and computational biology methods such as DARTS, CETSA, SPR, MS, molecular computational simulation, etc.
, And regulate its transcriptional activity
.

The study further found that another "undruggable" transcription factor, c-Myc, can also be inhibited by rapamycin through multidimensional proteomics data
.

Finally, in the tumor cell line xenograft model, it was found that the tumor growth was significantly inhibited in the mice treated with rapamycin for a long time, and the expression of STAT3 and c-Myc in the tumor was also significantly reduced

Figure 1.
Rapamycin targets STAT3 and inhibits its transcriptional activity

Figure 1.
Rapamycin targets STAT3 and inhibits its transcriptional activity Figure 1.
Rapamycin targets STAT3 and inhibits its transcriptional activity

This study shows for the first time that STAT3 is another new functional target of rapamycin in cells besides mTOR
.

Rapamycin inhibits its transcriptional activity by targeting STAT3 and affects the expression of c-Myc related genes

mTOR, STAT3 and c-Myc are all important drug targets in tumor treatment.
STAT3 and c-Myc are traditionally regarded as "non-drugable"
.

This study demonstrates that rapamycin object while having the ability to inhibit these three oncogenes, can play a "kill three birds" synergy, to achieve anti-tumor

Rapamycin has the ability to inhibit these three oncogenes at the same time, and can play a synergistic effect of "one arrow and three birds" to achieve the purpose of anti-tumor

Original source:

Original source:

Le Sun, et al.

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