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    Home > Medical News > Latest Medical News > Novarma, Bayer, etc. are developing IDH targets in the field of cancer treatment how much potential?

    Novarma, Bayer, etc. are developing IDH targets in the field of cancer treatment how much potential?

    • Last Update: 2020-10-05
    • Source: Internet
    • Author: User
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    In-cell carcinogenic metabolites (oncometabolites) caused by IDH mutations promote tumor development.
    recently published in Nature revealed a direct link between metabolic changes and genomic instability, two common features of cancer.
    this study provides new ideas for the development of tumor-targeted therapies based on IDH.
    currently, two IDH inhibitors, Idhifa and Tibsovo, have been approved for market worldwide, including Celgene, Novartis, Bayer, Keystone Pharmaceuticals, and Huang Medicine, Hai and Bio.
    other alternative approaches are beginning to receive attention, such as the development of potential therapies based on the activity of new enzymes formed by IDH mutations and third-stage drive gene changes.
    , we will introduce readers to the latest research advances in the field of IDH.
    IDH mutation and tumor isocric acid dehydrogenase (IDH) is the speed limit enzyme involved in cell energy metabolism in the human body, mainly IDH1, IDH2 and IDH3 subsypes.
    , mutations in the IDH1 and IDH2 genes cause the build-up of carcinogenic metabolites 2-hydroxypropyl diacids (2-HG) in cells.
    Because 2-HG is structurally similar to the alpha-ketone diacid (alpha-KG) molecule, the accumulation of 2-HG will compete with alpha-KG to bind to the catalytic site, thereby inhibiting some enzymes in the bioxygenase family.
    how tumour metabolites inhibit the repair of DNA damage (Photo Source: Resources) One of the lysine histones demethylase (KDM) modifies chromatin and catalytic DNA binding to the endolyine amino acid residue (K9) on histones 3 (H3).
    this effect is related to the 1o-dependent repair (HDR) pathway that repairs DNA double-stranded fractures.
    when a double strand of DNA breaks, H3K9 is methylated at the site of the injury, a local methylation signal that can help recruit DNA repair factors.
    , however, when the IDH mutation causes metabolites 2-HG to accumulate, the role of the enzyme is inhibited, which causes H3K9 high methylation throughout the genome.
    this will mask local methylation signals of H3K9 at the site of DNA damage, thereby hindering the recruitment of DNA repair factors.
    unresolted DNA double-stranded fractures can lead to genome instability, which in turn promotes tumor growth.
    studies have shown that IDH1 and IDH2 mutations have been found in a variety of tumors, including acute myeloid leukemia (AML), glioma, cartilage sarcoma, prostate cancer, melanoma and bile tube cancer.
    addition, IDH is included in the WHO Central Nervous System Classification Guidelines, a key gene that guides the classification and prognosis of gliomas in the brain.
    , IDH has become a hot research topic in the field of tumor therapy.
    is expected to be the birth of a new treatment strategy At present, the world has two IDH inhibitors approved for the market, in addition to the acute myeloid leukemia effective, it is also expected to become IDH1 mutation bile tube cancer patients of the new targeted therapy.
    , however, the potential treatment for tumors with IDH mutations goes far beyond that.
    in addition to developing inhibitors for IDH mutations, some studies have found that new enzyme activity based on IDH mutations can be used to find potential therapeutic targets for patients with IDH mutations, according to a 2018 article in Canser Cell.
    , targeted treatment for three-stage drive gene changes such as IDH1 R132H, which occurs during tumor progress, is also expected to be a potential method of tumor treatment.
    potential treatment strategies for IDH1/2 mutant malignancies (Photo Source: Reference 2) One of the more studied directions is synthetic death.
    know that using the principle of synthetic death, scientists have successfully developed PARP inhibitors that can prevent DNA damage repair to treat specific cancers.
    in synthetic death, cells tolerate the loss of individual gene functions, but the loss of gene combination function at the same time can lead to cell death.
    study found that tumor cells that produce metabolites 2-HG are particularly susceptible to death when treated with PARP inhibitors.
    , patients with gliomas with mutations in the IDH1 or IDH2 genes responded well to chemotherapy and radiotherapy combination therapies that induced DNA damage.
    shows that research and drug development for IDH still have great potential to be explored.
    this area is expected to lead to more new treatment strategies for tumors.
    two IDH inhibitors already on the market, several IDH inhibitors are already under development worldwide, according to public information.
    these products reduce the production of 2-HG by acting on IDH mutation points, inducing hismoglobin de-methylation, to achieve the effect of inhibiting tumor development.
    IDH1 inhibitors, IDH2 inhibitors and IDH1/IDH2 inhibitors, depending on the target of action.
    August 2017, Idhifa, the first IDH2 inhibitor brought in by Agios and New Base, was approved by the FDA to treat patients with relapsed/refractic AML with IDH2 gene mutations.
    about 8% to 19% of patients with AML had IDH2 mutations.
    mutation inhibits normal blood cell development, leading to too many immature blood cells.
    Idhifa controls disease development by inhibiting the mutant IDH2 protein.
    it's worth noting that the drug also won the best biotech product award at the 2018 Galen Awards.
    July 2018, ivosidenib, a world-first powerful, highly selective oral mutant IDH1 inhibitor discovered and developed by Agios, was approved for listing in the United States as the world's first IDH1 inhibitor.
    currently, the drug has been approved by the FDA to treat recurring or refractic AML detected to carry IDH1 mutations, as well as new diagnostic AML adult patients with specific conditions.
    addition, it has been identified by the FDA as a breakthrough therapy for the treatment of recurring or refragsive myeloid growth syndrome (MDS) that carries the IDH1 mutation.
    ivosidenib's mechanism of action (Photo: Reference 4) In addition to targeting AML patients, ivosidenib also reached its main endpoint in a global Phase 3 trial for bile tube cancer called ClariIDHyd.
    , nearly one-half of cases of bile tube cancer in the liver carry mutations in the IDH1 gene.
    show that patients with IDH1 mutations can benefit significantly from Tibsovo for life-threatening advanced bile tube cancer.
    In addition to the two products already on the market, there are several IDH inhibitors outside China that are currently at various stages of study, including Novarma's IDH305, Bayer's BAY1436032 and Forma Therapeutics' FT-2002.
    Keystone Pharmaceuticals, and Yellow Pharmaceuticals, Sea and Biology are being developed in China, and no targeted IDH inhibitors have been approved for market.
    but companies such as Keystone Pharmaceuticals, And yellow medicine, sea and biology, Saint and Pharmaceuticals are getting involved.
    , Keystone Pharmaceuticals has the fastest-growing ivosidenib from Agios and is currently conducting a number of registered trials, with applications for new drugs expected to be submitted in China in the first half of 2021.
    Cornerstone Pharmaceuticals: Ivosidenib, an IDH1 inhibitor discovered and developed by Agios, has been approved for market in the United States and has a clinical development and commercial interest in the drug in Greater China.
    in China, cornerstone pharmaceutical companies have submitted applications for new ivosidenib drugs in Taiwan in May 2019 and are expected to be approved by the market in 2020.
    , two registered trials of IDH1 mutation AML are also under way in China.
    , a registered trial of IDH1 mutation recurrence or resoicable AML is expected to be completed by 2020 and a new drug application will be submitted in China in the first half of 2021.
    and Yellow Medicine: HMPL-306 is an IDH1/2 dual inhibitor, the 9th independently developed innovative tumor drug for Huang Medicine, the proposed development of adaptive disorders with susceptible IDH1/2 mutations of blood tumors and solid tumors.
    , HMPL-306 is expected to address potential IDH mutant transformation.
    , the product's Phase 1 clinical trial in China completed its first patient deliveries in late July, and the company plans to submit its IND and start Phase 1 clinical trials in the U.S. in the next six months.
    HMPL-306 is one of the key development projects in the next wave of innovative development plans with Huang Medicine.
    and Biology: HH2301 is a new, efficient and specific mIDH1 inhibitor developed jointly by Haihe Bio and Shanghai Pharmaceuticals.
    preclinical studies have shown that it has excellent in vivo anti-tumor activity and good pharmacodynamic properties and safety in all test genus.
    May, the product was approved by FDA clinical trials to treat solid tumors with IDH1 mutations, including advanced bile tube cancer, cartilage sarcoma and glioma.
    Sanhe Pharmaceuticals: SH1573 capsules are independent research and development of Sanhe Pharmaceuticals, with independent property rights of IDH2 inhibitors, chemical drugs 1 class of new drugs, the main adaptive disorder is IDH2 mutation AML.
    June 2019, the product was successfully conducted in a multi-center Phase 1/2 clinical study in patients with relapsed or incurable AML with IDH2 mutations.
    , the company is currently conducting phase 1 clinical studies of SH1573.
    In addition, according to the drug clinical trial registration and information publicity platform, the first class of new drug TQB3455 tablets jointly declared by Zhengda Tianqing and Selintai Pharmaceuticals has been registered in China to carry out 3 Phase 1 clinical trials for patients with advanced malignant solid tumors or blood tumors, as well as IDH2 gene mutations of solid tumors and AML.
    References: Chen L L, Xiong Y . Tumour metabolites hinder DNA repair. Nature, 2020. Waitkus M S, Diplas B H, Yan H . Biological Role and Therapeutic Potential of IDH Mutations in Cancer. Cancer Cell, 2018: S153561081830182X. David H. Ilson, MD, PhD reviewing Abou-Alfa GK et al. A New Therapy Targeting IDH-1 Mutations for Cholangiocarcinoma. Lancet Oncol, 2020 Jun (4) Popovici-Muller et al., (2018). Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Addor for The Treatment of IDH1 Mutant Cancers. ACD Medicinal Chemistry Letters. DOI: 10.1021/acsmedchemlett.7b00421 ( 5 ) Sea and Bioinspicive Drug IDH1 inhibitors are tacitly licensed by FDA clinical trials. Retrived May 7 2020, from the sea and biology HaiHe Biopharma (6) St. and Pharmaceuticals SH1573 capsule clinical program seminar successfully held. Retrived Jun 26 2019, from the company's official website and public information.
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