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    Home > Medical News > Medical World News > Innovative pharmaceutical companies accelerate the layout of CDK4/6 target inhibitors

    Innovative pharmaceutical companies accelerate the layout of CDK4/6 target inhibitors

    • Last Update: 2021-01-17
    • Source: Internet
    • Author: User
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    According to the Drug Review and Evaluation Center (CDE) of the State Drug Administration of China, 41 new clinical trial applications were approved for "implied licensing" in the second week of November 2020, involving 10 new drugs being developed in the field of cancer, including two CDK4/6 inhibitors, SHR6390 tablets from Hengrui Pharmaceuticals and BEBT-209 capsules from Bibert Pharmaceuticals.
    Henri SHR6390 combined fluorovirs group second-line therapy - hormone-positive (HR-plus), human skin growth factor-negative (HER2-), i.e. HR-/HER2-advanced breast cancer therapy in 2019 has entered multi-center Phase III clinical research.
    Hasbro Pharmaceuticals has registered 10 clinical studies on SHR6390, targeting adaptations including breast cancer, melanoma and advanced solid tumors.
    SHR6390 this clinical trial is implied to target the indications: combined endocrine therapy for the early or localized advanced breast cancer of HR-/HER2- complementary treatment.
    BeBT-209 is a selective CDK4/6 inhibitor that may increase ability by increasing maximum absorption of compounds and appropriately reducing half-life.
    addition, by reducing CDK6 inhibition activity and improving CDK4 selection activity, reducing CDK4/6 inhibitor blood system and immunosuppressive toxicity may make BEBT-209 safer and more effective.
    beBT-209 This approved clinical study is suitable for: combined fluorovis group therapy for the progression of the disease after endocrine treatment of HR-/HER2-advanced breast cancer.
    November 18, china's State Drug Administration Drug Review Center (CDE) announced that a new class 1 drug injection-injection Trilaciclib clinical trial jointly declared by Synth Pharmaceuticals and G1 Therapeutics was accepted. First-in-class" CDK4/6 inhibitors, FDA-mandated priority review qualifications and breakthrough therapies for small cell lung cancer (SCLC) adaptations, are also under way for clinical studies of triple-negative breast and colon cancer.
    It is worth noting that clinical studies of small cell lung cancer (SCLC) have found that Trilaciclib, through a short period of G1 blocking, can relieve bone marrow inhibition caused by chemotherapy, protect hematocytes/subgeneration cells and the immune system, and can therefore be incorporated into a variety of chemotherapy options.
    august this year, Synractic Pharmaceuticals acquired a $170 million interest in the development and commercialization of all adaptations in Greater China.
    addition, G1 Therapeutics has another oral CDK4/6 inhibitor, lerociclib, which is conducting clinical studies of non-small cell lung cancer (NSCLC) with a mutant type of skin growth factor (EGFR).
    in the domestic breast cancer innovative drug market, led by Hengrui, more and more Chinese innovative pharmaceutical companies to join the CDK4/6 hot target competition.
    Figure 1: CDK-Rb-E2F pathways regulate cell cycle sources: public information, and cell cycle protein-dependent kinases 4 and 6 (CDK4/6) of the Zhongkang Industrial Capital Research Center are the key regulatory factors for cell division and proliferation.
    CDK4/6 is combined with the cell cycle protein D (Cyclin D) to phosphate the retinal scleroblast protein (Rb), releasing the transcription factor E2F.
    E2F promotes the transcription of genes associated with cell cycles by binding to its DPs, allowing cells to enter the DNA replication phase (S1 phase) from the pre-DNA synthesis stage (G1) of the cell cycle.
    p16, p21, and p27 proteins in cells inhibit the activity of CDK family proteins, while in estrogen-positive ER-breast cancer patients, CDK4/6 downstream of the ER signaling path is overactive.
    clinical studies have found that CDK4/6 and estrogen-like ER signaling double inhibitors can effectively block the excessive proliferation of such breast cancer cells.
    addition, rb protein is an important tumor suppressor, and mutations or absences are often found in multiple tumors by inhibiting the active blocking cell cycle of E2F in a variety of cells.
    currently about $20 billion in the global breast cancer drug market, and is projected to grow at a compound rate of about 11 percent by 2025 to $38.4 billion.
    's current market for breast cancer treatment drugs, led by Hercetin (CurtoJudan), is aimed primarily at HER2 plus breast cancer patients, with sales of $7.1 billion in 2018, followed by CDK4/6 inhibitor Palbociclib, trade name Iberance/Eboxin), PatoJudan, yew alcohol and mTOR inhibitor Ivemos.
    Since HR plus/HER2 is the most common molecular subtype of breast cancer, accounting for more than 60% of all breast cancer patients, inhibitors targeted at CDK4/6 have received the attention of multinational pharmaceutical giants since they were approved for market in 2015.
    According to the Grand View Research report, CDK4/6 inhibitors are expected to have sales of more than $4 billion by 2020, with a much faster market growth rate than HER2 targeted drugs, and the future U.S. breast cancer drug market will be dominated by CDK4/6 and HER2 targeted drugs.
    Chart 2. U.S. Breast Cancer Drug Market Growth Forecast Source: Grand View Research, Zhongkang Industrial Capital Research Center, three CDK4/6 inhibitors are currently approved for listing worldwide: Pfizer's Palbociclib, Novarma's Ribociclib, commodity name Kisqali and Lilly's Abemaciclib.
    Pfizer's Pfizer," which went public in 2015 as the first CDK4/6 inhibitor, scored $723 million in its first year and has since maintained a high growth rate.
    's Riposili and Lilly's Abesili are listed in 2017, and their market share is growing rapidly.
    with the expansion of adaptive disorders, the future is expected to form a three-legged trend.
    All three drugs are suitable for menoptocratic patients with advanced or metastasis breast cancer in HR-/HER2, where first-line treatment requires a combination of aromatase inhibitors (AI) such as anatrophic and virulent, and second-line treatment requires a combination of estrogen-subject antagonist Fulvestrantest.
    clinical study data show that three CDK4/6 inhibitors can significantly improve objective efficiency and prolong patients' progression-free lifetime (PFS), whether first- or second-line, pre-menopenerial or post-menopenerial.
    in first-line treatment, all three CDK4/6 inhibitors can extend progression-free survival (PFS) by more than 10 months.
    second-line treatment with progression after endocrine therapy, the efficacy risk ratio of fluorovis group and CDK4/6 inhibitors was between 0.5 and 0.6, i.e. reduced the risk of disease progression by about 40% to 50%.
    Taking the placebo-controlled randomized double-blind clinical Phase III trial of Abersili's MONK 3 as an example, patients with advanced breast cancer who received a combination of abersili and aromatase inhibitors had a non-progressive survival period (PFS) of 28.2 months, significantly higher than the combination of placebo and aromatase inhibitors (14.8 months).
    in patients with measurable tumor size, the objective remission rate (ORR) was 55.4% in patients treated with a combination of abersili and aromatase inhibitors.
    52.1% of the patients were partially relieved, while 3.4% were fully relieved.
    orR was 40.2% in patients who received a combination of placebo and aromatase inhibitors, and the patients were partially relieved.
    Chart 3. Clinical results of the three CDK4/6 inhibitors are sourced from: 2018 ASCO, China Kang Industrial Capital Research Center in the CDK4/6 inhibitor research and development and patent application boom, also appeared from the Shanghai Institute of Pharmaceutical Research, China Pharmaceutical University, Nanca University and other academic research institutions of Chinese scholars.
    recently, a team of professors at Nanca University's School of Pharmacy, Yang Cheng, designed and synthesized PROTAC molecules that simultaneously degrade CDK2/4/6 in cancer cells by connecting Pomadamide and Rebersili derivatives.
    the compound increased the oral bioavailableness of CDK4/6 inhibitors from less than 1% to 68%, and is the best bioavailable PROTAC molecule reported in the literature.
    and this inhibitor degrades the CDK4/6 protein, it also degrades the CDK2 protein, thereby suppressing the potential drug-resistant CDK2-CyclinE path path.
    Although oral bio-utilization reached 68%, the efficiency of its degradation protein is not high, in animal trials oral 200 mg/kg, tumor suppression rate of only 60%, this may be due to the compound is large, there is a distribution problem from the blood into tumor tissue.
    addition, the study combined CDK4/6 target with the rapid development of PROTAC technology in recent years to design and degrade CKD2/4/6 PROTAC molecules simultaneously, providing a feasible method for improving the oral bio-utilization of CDK4/6 inhibitors.
    4. Fast follow for Chinese scientists Source: First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo, Yang et al; CDK4/6 targeted treatment research and clinical applications have made great progress, innovative pharmaceutical companies are also actively layout and expand the role of CDK4/6 inhibitors in other subtypes of breast cancer and non-small cell lung cancer, I believe in the near future is expected to see CDK4/6 inhibitors are more widely used for the benefit of more cancer patients.
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