Dual-mechanism estrogen receptor inhibitors against breast cancer treatment resistance
Dual-mechanism estrogen receptor inhibitors against breast cancer treatment resistance
According to the pathological classification, about 70% of breast cancer patients are estrogen receptor (ER) positive, and they all need to receive endocrine therapy clinically
Recently, the Proceedings of the National Academy of Sciences (PNAS) of the United States published online the latest results completed by non-United Nations scientific research units in the School of Life Sciences of Hubei University and the State Key Laboratory of Biocatalysis and Enzyme Engineering jointly established by the provincial and ministerial departments
Drug resistance seriously threatens breast cancer treatment
Drug resistance seriously threatens breast cancer treatment "Estrogen can regulate a variety of physiological processes, such as cell growth, proliferation, development and differentiation
Kendall Nettles, the corresponding author of the paper and a researcher at The Scripps Research Institute in the United States, said: "In the past few decades, people have devoted themselves to studying the potential mechanism of estrogen signaling pathways in breast cancer, and developed anti-estrogens.
At present, estrogen receptor inhibitors are commonly used clinically, as the main drugs for endocrine therapy, and play an indispensable role in the treatment of estrogen receptor-positive breast cancer
However, John Katzenellenbogen, the co-corresponding author of the paper and a professor at the University of Illinois at Urbana-Champaign, said that with the widespread use of estrogen receptor inhibitors, most patients develop drug resistance during treatment, which stops the drug’s killing effect on cancer cells.
"Drug resistance is one of the main reasons for the failure of breast cancer treatment, which leads to the rapid recurrence or deterioration of the cancer, and ultimately the death of the patient
"Direct antagonism" does not defeat resistance
"Direct antagonism" does not defeat resistance According to Min Jian, estrogen receptor inhibitors are mainly divided into two categories
One type is selective estrogen receptor modulators (SERM).
The other type is selective estrogen receptor downregulator (SERD), which can significantly reduce the level of estrogen receptor protein, such as Fulvestrant
Min Jian emphasized that the above-mentioned drugs can only partially inhibit the activity of estrogen receptors, and they all contain a single precisely positioned chemical side chain
"This kind of drug mechanism that interferes with helix 12 through direct spatial contact, thereby exerting an inhibitory effect, is called'direct antagonism'
Chemical structure of representative drugs Photo courtesy of interviewee
Chemical structure of representative drugs Photo courtesy of interviewee "If cancer cells are regarded as a city to be conquered, the estrogen receptor is the city gate, and the ligand binding domain on the estrogen receptor is equivalent to a lock, and therapeutic drugs are a key we have
This new key is the "indirect antagonism" mechanism discovered by the team in the research
.
Two-pronged approach to unlock new locks
Two-pronged approach to unlock new locks Nettles said that their research has screened a lot of compounds, hoping to find new breast cancer treatment drugs
.
Finally, we have observed uniqueness in a series of compounds with 5,6-diaryl-7-oxobis[2.
2.
1]cyclohept-5-ene N-arylsulfonamide (OBHSN) structure as the core Indirect antagonism" mechanism
.
The detailed crystal structure analysis shows that the above compounds do not need to "directly antagonize" the chemical side chain, only the aromatic ring linked by sulfonamide affects the position of the adjacent helix 11 of the key helix 12, thereby indirectly affecting the correct positioning of the helix 12.
To obtain complete inhibition of wild-type breast cancer cells, this unique mechanism is called "indirect antagonism
.
"
A) Drug design concept; B) Compounds 27 and 29 effectively inhibit the proliferation of MCF-7
.
Photo courtesy of the interviewee
A) Drug design concept; B) Compounds 27 and 29 effectively inhibit the proliferation of MCF-7
.
Photo courtesy of the interviewee In order to design a unique "new lock" to solve the drug-resistant protein after mutation, the team of researchers added specific groups to cause indirect antagonism in addition to the side chain used for direct antagonism in drug design.
Two different molecular elements, direct antagonism and indirect antagonism, are designed on one compound
.
"We have designed and synthesized a series of dual-mechanism estrogen receptor inhibitors (DMERIs), of which the two most potential compounds specifically target estrogen receptors in breast cancer cells, and have very significant killing effects on breast cancer cells.
It is especially effective in various drug-resistant cell models
.
" Min Jian said
.
Biological activity of DMERI compound in breast cancer resistance model
.
Photo courtesy of the interviewee
Biological activity of DMERI compound in breast cancer resistance model
.
Photo courtesy of the interviewee In order to further study the structural biology mechanism behind the antagonism of dual-mechanism estrogen receptor inhibitors, they conducted a lot of structural biology research
.
The team found that one of the dual-mechanism estrogen receptor inhibitors produced huge interference to helix 12, making a surface in the ligand binding domain more open and accessible, easier to bind co-inhibitors, and more complete to cancer cells.
Antagonism of proliferation
.
X-ray diffraction crystal structure analysis and research results of hydrogen-deuterium exchange mass spectrometry
.
Photo courtesy of the interviewee
X-ray diffraction crystal structure analysis and research results of hydrogen-deuterium exchange mass spectrometry
.
Photo courtesy of the interviewee "This research goes beyond the traditional fixed thinking and greatly expands the potential design principles of the compound side chain that is not the main driving factor for antagonism.
It combines two chemical targeting methods-direct antagonism and indirect antagonism into a single compound.
Make it a potential breast cancer treatment drug
.
We have also explored the structural mechanism of dual-mechanism estrogen receptor inhibitors, providing a flexible platform for new estrogen receptor-directed therapies and endocrine-resistant breast cancer The research and development of drugs opened up new ideas
.
" Min Jian said
.
Related paper information: https://doi.
org/10.
1073/pnas.
2101657118
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