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On September 15, 2022, Yang Caiguang's research group of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences and the Chemical Biology Research Center of the Hangzhou Advanced Research Institute of the National University of Science and Technology was held in Cell Chemical Biology A research paper
entitled "Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma" was published.
The study reports a new class of skeleton ClpP small molecule agonists and conceptually demonstrates that abnormal activation of ClpP disrupts mitochondrial proteome homeostasis as a worthwhile pancreatic cancer treatment strategy
.
entitled "Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma" was published.
The study reports a new class of skeleton ClpP small molecule agonists and conceptually demonstrates that abnormal activation of ClpP disrupts mitochondrial proteome homeostasis as a worthwhile pancreatic cancer treatment strategy
.
ClpP is a highly conserved serine proteolytic enzyme that is widely found in
prokaryotes and eukaryotes.
Early collaborative study of structure and mechanism of Staphylococcus aureus ClpP in Yang Caiguang's research group (J Biol Chem, 2011, 286, 37590; J Biol Chem, 2013, 288, 17643; ACS Chem Biol, 2016, 11, 1964), a recent chemical intervention study on ClpP of rice leaf blight (J Agric Food Chem, 2021, 69, 7545), revealed potential new targets for the discovery of new drugs resistant to bacterial leaf blight infection in rice
.
prokaryotes and eukaryotes.
Early collaborative study of structure and mechanism of Staphylococcus aureus ClpP in Yang Caiguang's research group (J Biol Chem, 2011, 286, 37590; J Biol Chem, 2013, 288, 17643; ACS Chem Biol, 2016, 11, 1964), a recent chemical intervention study on ClpP of rice leaf blight (J Agric Food Chem, 2021, 69, 7545), revealed potential new targets for the discovery of new drugs resistant to bacterial leaf blight infection in rice
.
As the "energy factory" of cells, mitochondria are important sites for
various biochemical reactions such as oxidative phosphorylation (OXPHOS) and the tricarboxylic acid cycle within cells.
Currently, inhibiting respiratory chain complex intervention in OXPHOS function is an emerging tumor treatment strategy
.
The human serine hydrolase ClpP is strictly positioned in the mitochondrial matrix, timely clears the wrong or abnormal proteins in the mitochondria due to stress pressure, etc.
, and plays an important function
in maintaining the homeostasis of mitochondrial proteins.
Functional disorders of ClpP cause homeostasis disorders of respiratory chain complexes, inhibit OXPHOS function, cause proteinotoxic stress and cell death
.
Targeted intervention ClpP is a new direction in potential anti-tumor research, but it is unclear
whether ClpP small molecule agonists can fight pancreatic cancer.
The development of new types of ClpP agonists for tumor biology and chemical biology research is of great significance
for understanding mitochondrial protein homeostasis and promoting the discovery of new drug candidates.
various biochemical reactions such as oxidative phosphorylation (OXPHOS) and the tricarboxylic acid cycle within cells.
Currently, inhibiting respiratory chain complex intervention in OXPHOS function is an emerging tumor treatment strategy
.
The human serine hydrolase ClpP is strictly positioned in the mitochondrial matrix, timely clears the wrong or abnormal proteins in the mitochondria due to stress pressure, etc.
, and plays an important function
in maintaining the homeostasis of mitochondrial proteins.
Functional disorders of ClpP cause homeostasis disorders of respiratory chain complexes, inhibit OXPHOS function, cause proteinotoxic stress and cell death
.
Targeted intervention ClpP is a new direction in potential anti-tumor research, but it is unclear
whether ClpP small molecule agonists can fight pancreatic cancer.
The development of new types of ClpP agonists for tumor biology and chemical biology research is of great significance
for understanding mitochondrial protein homeostasis and promoting the discovery of new drug candidates.
Based on data analysis, the research team found that the high expression of CLPP gene was positively correlated with the prognosis of pancreatic cancer patients, and the abundance of ClpP protein in pancreatic cancer tissues was significantly higher
than that of normal tissues.
Cell level and animal model studies based on genetic manipulation have demonstrated that the enhancement of ClpP hydrolytic activity significantly inhibits the proliferation and tumorigenesis of pancreatic cancer cells, indicating the feasibility
of ClpP activity excitation anti-pancreatic cancer.
The new skeleton of ClpP agonist ZG111 was obtained by high-throughput screening combined with synthetic optimization, which activated the function of ClpP proteolytic enzyme in pancreatic cancer cells of different KRAS genotypes, interfered with the homeostasis of mitochondrial respiratory chain complex, and indirectly inhibited the proliferation
of antipancreatic cancer cells with OXPHOS function.
ZG111 has a good antitumor effect on xenografted pancreatic cancer models with different KRAS genetic backgrounds, indicating that the dysfunctional activation of ClpP may be a potential treatment strategy for
pancreatic cancer.
than that of normal tissues.
Cell level and animal model studies based on genetic manipulation have demonstrated that the enhancement of ClpP hydrolytic activity significantly inhibits the proliferation and tumorigenesis of pancreatic cancer cells, indicating the feasibility
of ClpP activity excitation anti-pancreatic cancer.
The new skeleton of ClpP agonist ZG111 was obtained by high-throughput screening combined with synthetic optimization, which activated the function of ClpP proteolytic enzyme in pancreatic cancer cells of different KRAS genotypes, interfered with the homeostasis of mitochondrial respiratory chain complex, and indirectly inhibited the proliferation
of antipancreatic cancer cells with OXPHOS function.
ZG111 has a good antitumor effect on xenografted pancreatic cancer models with different KRAS genetic backgrounds, indicating that the dysfunctional activation of ClpP may be a potential treatment strategy for
pancreatic cancer.
Pengyu Wang, Ph.
D.
candidate, Dr.
Zhang Tao, assistant researcher, and Dr.
Wang Xinjing, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, are co-first authors
of the paper.
Yang Caiguang, a researcher at the Shanghai Institute of Medicine, is the corresponding author of
the paper.
The research was supported by Gan Jianhua Research Group and Zhou Lu Research Group of Fudan University, Yang Song Research Group of Guizhou University, Lu Xiongxiong's Research Group of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Zhang Yonghui Research Group of Tsinghua University, and Shanghai Synchrotron Radiation Light Source and Pilot Special Compound Resource Bank, and was funded
by the National Natural Science Foundation of China.
D.
candidate, Dr.
Zhang Tao, assistant researcher, and Dr.
Wang Xinjing, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, are co-first authors
of the paper.
Yang Caiguang, a researcher at the Shanghai Institute of Medicine, is the corresponding author of
the paper.
The research was supported by Gan Jianhua Research Group and Zhou Lu Research Group of Fudan University, Yang Song Research Group of Guizhou University, Lu Xiongxiong's Research Group of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Zhang Yonghui Research Group of Tsinghua University, and Shanghai Synchrotron Radiation Light Source and Pilot Special Compound Resource Bank, and was funded
by the National Natural Science Foundation of China.
Original link:molecules agonize ClpP to disrupt mitochondrial function against pancreatic cancer
(Contributed by Yang Caiguang Research Group)
