PNAS: Has Ray Gongto become a targeted drug? It is expected to be used to treat cancers with IDH1 mutations

In the history of medicine, there are many classic pharmaceutical ingredients from natural plants, such as the "unfailing willow" aspirin, "the change of god medicine" metformin.
So now, we're looking for an anti-cancer mechanism for a natural compound, and interestingly, this compound from classic Chinese medicine is probably a target drug that can break through the particularly difficult cancer gene IDH1 mutation.
the paper, published recently in the Proceedings of the National Academy of Sciences, was co-authored by Xu Guowang of the Dalian Institute of Chemical Physics of the Chinese Academy of Sciences and Yang Chunzhang of the National Cancer Institute of the United States.
researchers found that the main active ingredient in Tripterygium wilfordii, Regutens, was able to cause cancer cells with IDH1 mutations to die of oxidative stress by inhibiting the Nrf2-related glutathione synthesis path.
first recorded in detail, it appeared in the form of poison.
Qing Dynasty, "the herb outline to pick up the relic" records: "the poisonous fish, where the snail is also dead, its nature is the strongest, with its grass smoke silkworms are not born."
" is a big new hope for cancerous species such as gliomas, which IDH1 inhibitors have been unable to take for a long time.
(Photo: InnerPath) isochlic acid dehydrogenase (IDH1/2) mutation is a very common cancer gene mutation that occurs in gliomas, acute myeloid leukemia, bile tube cancer, cartilage sarcoma, and pancreatic cancer.
mutations in IDH1 can cause changes in enzyme activity, whether IDH is a very critical enzyme in metabolism, which causes the IDH1 mutation to directly affect triacetic acid circulation, oxidation balance, and energy metabolism.
, about 6% to 10% of AML patients have isocric acid dehydrogenase (IDH)1 mutation.
In fact, Mays Medicine has previously reported that: STM: Chinese medicine ingredient Rai gongto meth can fight pancreatic cancer, AJP: Lei Gongto extract by activating endostropheric stress to kill pancreatic cancer cells, but this article directly led Lei Gongto methionin to the possibility of "targeted drugs."
addition, inhibitors targeting IDH1 have been developed for a long time, showing good results in blood tumors, and in 2018 Agios developed a targeted new drug, Tibsovo (ivosidenib), which has been approved by the FDA for recurring or refractic acute myeloid leukemia (R/RML) adult patients with mutations susceptible to isocyclic acid dehydrogenase-1 (IDH1).
addition, Tibsovo's brother drug, Enasidenib, the first IDH2 inhibitor, was approved by the FDA in August 2017 to treat recurring/refractic acute myeloid leukemia with IDH2 mutations.
addition, ivosidenib, which showed significant efficacy in the clll phase clinical trial of bile tube cancer, significantly improved the progression-free survival (PFS) of patients with bile tube cancer by 2.7 months, extended the total lifetime to 10.8 months, and reduced the risk of death by 63%.
these two drugs do not respond well in solid tumors such as gliomas and cartilage sarcoma.
can we do to overcome this difficulty? It depends on how the IDH1 mutation changes the cells.
researchers first induced the cell's IDH1 mutation with strong mycomycin (Dox), and found that 24 hours after the mutation occurred, the level of reactive oxygen (ROS) in the cell increased significantly, which increased the oxidation levels of large molecules such as lipids.
similar oxidative stress was found in brain tumor cells from patients.
Dox-induced mutations have the pros and cons of increasing oxidative stress at Ros levels, which can help kill pathogens that invade cells, but oxidation levels are too high, which in turn causes cells to "martyr" together.
is there any way we can take advantage of this feature of IDH1 mutation cancer cells and let it live on its own? Of course, cells are certainly not stupid, they have their own set of antioxidant means, including the nuclear factor-related factor 2 (Nrf2) regulation of the well-known antioxidant, glutathione.
sure enough, the researchers found that Nrf2 transcription activity increased by 2-3 times in cells carrying IDH1 mutations, and that downstream antioxidant-related genes such as GCLC, GCLM, SLC7A11, NQO1, etc. were very active, indicating that the antioxidant path path of Nrf2 regulation was significantly activated.
notable, SLC7A11 was the most significantly increased, with a 7x higher level of expression than normal IDH1 cells! This SLC7A11, unsurprisingly, is the key to cell synthesis of glutathione from the beginning! It is because of SLC7A11 that IDH1 mutant cells are protected from apoptosis.
silence SLC7A11 makes a large number of apoptosis of the cells is now the turn of Lei Gongto meth.
TPL is a cyclodephate compound that exhibits strong transcription inhibition at the namore level.
, the researchers found that genes inhibited by retocin actually re-matched a large number of downstream genes in Nrf2.
right, including the SLC7A11.
the chemical structure of Lei Gongto methyl is very logical next.
indust, Nrf2-mediated glutathione synthesis was inhibited, and the elevated ROS in the IDH1 mutant cells was unresponsive, gradually leading to oxidative damage to large molecules such as DNA and lipids, and eventually apoptosis.
Regongto meth, also known as Leigongto esters, Leigongto estersol, is a kind of epoxy niobium compound extracted from the roots, leaves, flowers and fruits of the wei spear plant Leigongto, with Lei gongto base, Leigong fuji sub-alkali, Leigong fuji base, Alkaloids such as Leigongto Iv base, Leigong Fuji added alkali and Leigong Fujimin alkali constitute the main active ingredient of Leigongto extract This effect is very selective to IDH1 mutant cells, after the application of Leigongto meth, the proliferation of IDH1 mutant cells decreased by 75%, while normal cells have little observed effect.
normal cells (left) were virtually unaffected in heterogeneic transplanted mouse models, and the application of retocin greatly extended the survival of mice.
limitation of the study, which greatly prolonged the survival of mice, was that the inhibitory mechanism of Nrf2 was not fully understanding, and adverse reactions and the ability to penetrate the blood-brain barrier required further study.
look forward to quickly to find out these problems, let it go to clinical applications! Mace medical search data found that the recent international research on ratonin is very hot, including rheumatoid, tumor, immunity and other fields.
in the tumor, for oral cancer, bile tube cancer and so on have some research, but also found that it can inhibit the expression of PD-L1.
a recent review published on Nat Prod Rep provides a comprehensive overview of the main developments in the last 20 years, and deserves to be read in depth.
, however, Mays Medical Editor also cautions that this is only a preliminary study and is still quite far from clinical.
Even if Lei Gongto meth is an inhibitor of IDH1 mutation, it may not be effective for all IDH1 mutation tumors, from the previously approved IDH1 inhibitors, the effect on blood tumors is good, but for other IDH1 mutations of the solid tumor effect still needs to be studied, in addition, through the blood-brain barrier, the role of central tumors, also need to be considered.
in short, a drug may eventually be clinically possible to carry out a large number of chemical modifications, dosage form modifications and so on.
addition, Mays medical editor-in-chief believes it is too early to draw conclusions as to whether Regongto meth can be a targeted drug.
should also be further confirmed through structural biology, whether Thermotocin is directly acting on the IDH1 mutation, and IDH1 mutation protein interaction, in order to be more reliable.
difference between the chemical structure of the first IDH1 inhibitor is considerable.
chemical structure of IDH1-specific inhibitor Ivosidenib