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    Home > Medical News > Medical World News > The latest development of the world's first PROTAC drug ARV-110 and the pipeline layout are brief.

    The latest development of the world's first PROTAC drug ARV-110 and the pipeline layout are brief.

    • Last Update: 2020-08-03
    • Source: Internet
    • Author: User
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    L-Day protein degradation target ingenuated protein degradation target chimeras (proteolysistargeting chimeras, PROTAC) is a very hot drug development technology, the industry is considered by the industry as a small molecule drug research and development of the big killer.
    one end of this type of dual-function small molecule is a ligand that targets the target protein, and the other end is a ligand binding E3 ubiquitin joining enzyme, which is then connected by a certain length of linker.
    in the body, the target protein and E3 ubiquitin joinula can be close, so that the target protein is ubiquitin-labeled, and then by ubiquitin-protease pathway degradation.
    its main advantages are as follows: 1, targeted degradation "non-medicinal targets" such as KRAS, STAT3, etc.;
    the technology has been in the process for 20 years, and in 1999 researchers at Proteinix filed a patent application for the use of ubiquitin mechanisms to degrade specific proteins using small molecular compounds.
    two years later, Craig Crews and Dr. Raymond Deshaies designed a series of two-function small molecule-induced metaxadepeptide 2 (MetAP-2) degradation based on peptide compounds and formally introduced the PROTAC concept.
    the first generation of PROTACs failed because these compounds, which act together based on large, bulky peptides, were difficult to enter the cells.
    Until 2008, the Crews team designed a second-generation PROTACs based on E3's ubiquitin-protein-nexuse MDM2 that can be used to degrade androgen receptors (AR).
    2015 the Crews team designed a new generation of PROTACs that reduced levels of multiple proteins by more than 90%, based on the new E3 ubiquitin connectivee VHL and CRBN ligands.
    that year, Novartis's head of research and development, James Bradner, in Science, published a new generation of thalidomide-based PROTAC molecules, which exploded the field.
    Crews in 2013 established Arvinas, the world's first drug research and development company using PROTAC technology.
    is optimistic about this technology, the company developed the world's first PROTAC drug ARV-110, intended to be used for the treatment of dedegeneration resistance prostate cancer, has entered the clinical Phase I phase of the study phase, clinical I initial data show that ARV-110 has good oral utilization and good safety and tolerance.
    Figure 1: Protein degradation targets the mechanism of the mechanism of chimeric.
    from Reference 1 about ARV-110ARV-110 is Arvinas' first oral bioavailable PRAOTC small molecule drug in the field of protein degradation-targeted chima, selectively targeted to degrade male hormone receptors (AR).
    obtained FDA Fast Track Approval in May 2019 for a rv-110, primarily for the treatment of metastatic trend-resistant prostate cancer (mCRPC).
    in developed Europe and the United States, mCRPC is the second highest incidence of malignant tumors in men, but also has been the field of prostate cancer treatment difficulties and clinical research hot spots.
    currently targeted at male hormone receptor targets (AR) for first-line therapeutic drugs such as abitron and enmesyamine.
    in addition, the American Society of Clinical Oncology's Society of Urology Cancer Symposium (ASCO-GU2020) in March 2020 discussed the tendency to use abitron in first-line treatment for mCRPC patients carrying DNA damage repair mutations (DDM) to have better therapeutic effects than using heterosulpin.
    targeting androgen receptors (ARAT) drugs (abitron or enmelyumeite) for first-line treatment in mCRPC patients will benefit patients more from survival, especially in patients with the prostate catheter cancer (IDC-P) subtype.
    however, for patients with AR gene or gene enhancer amplification or AR-point mutation, the current first-line therapeutic drug is less effective, 15-25% of patients do not respond to second-generation hormone therapy such as abitron and enmelyume, and most reactive patients end up with severe drug resistance, leading to poor prognosis. the PRAOTC molecule ARV-110, which
    targets degradation of androgen receptors, is currently showing excellent activity in clinical models of AR mutation and overexpression.
    Figure 1: Introduction to ARV-110.
    derived from Reference 2 mechanisms to overcome these challenges and improve current treatment options, ARV-110 distinguishes traditional inhibitors from using the ubiquitin-protease system to degrade AR proteins that play a key role in prostate cancer development, without the need to inhibit their function by "occupying" receptors.
    , the PROTAC drug can also work repeatedly to degrade the newly transcribed target protein, thus overcoming the increase in target protein expression and mutations in the target protein.
    specific molecular structure has not yet been announced.
    preclinical studies in preclinical studies, ARV-110 has shown promising activity as a target degradation agent for AR.
    in a model sensitive to enmyleamine, ARV-110 showed a reduction in prostate-specific antigens (PSA) similar to enmelyumine and a lower dose of the drug.
    in the enthroamine resistance model, ARV-110 can significantly inhibit tumor growth.
    Figure 2: Preclinical data for ARV-110.
    from Reference 2 Clinical Trials on May 29, 2019 FDA approved a phased, open-label, dose-increasing clinical Phase I trial to evaluate the safety, tolerance, pharmacokinetics, and pharmacology of ARV-110 in patients with metastatic derebelating prostate cancer who have previously received at least two systemic therapies.
    the trial is expected to involve 36 patients aged 18 years and older and receiving at least two approved CRPC systemic therapy (at least one must be abitron or enmesy.
    patients with transsexual mCRPC must undergo ADT (prostate prostate cancer androgen deprivation therapy) or testicular ectomy with gonadotropin-releasing hormone analogues or inhibitors.
    Clinical Update Data On May 13, 2020, the latest safety data and early efficacy data for Phase I Clinical Trials (NCT03888612) were published in a summary of the American Clinical Oncology School Year (ASCO).
    to determine the maximum tolerable dose (MTD) and the recommended dose of Stage 2 (RP2D) for the determination of a maximum tolerable dose of ARV-110, and to orally a daily oral ARV-110 for mCRPC patients who have previously received at least 2 treatment options, including enmelyamine and/or abitron.
    endpoints include dose-limiting toxicity (DLT), adverse events (AEs), pharmacokinetics (PK), biomarkers (e.g. AR mutation analysis), RECIST (solid tumor efficacy evaluation criteria) and PSA (prostate-specific antigen) reactions.
    as of January 2020, 18 patients participated in the trial, the dose was divided into 4 groups: 35 mg (3 cases), 70 mg (4 cases), 140 mg (8 cases), 280 mg (3 cases).
    12 of the patients had previously been treated with ethluamine and abitron at the same time, while 14 had undergone chemotherapy treatment. One in 18 patients in the
    developed level 4 (Gr) dose-limiting toxicity (DLT, 280 mg) while taking the cholesterol drug Rosuvastatin, and an increase in hepatic transaminase AST/ALT, followed by acute renal failure.
    the second patient developed a level 3 (Gr) dose limiting toxicity and an increase in hepatometmathane AST/ALT while taking the cholesterol drug rishuavastatin, and a further ARV-110 treatment was continued after discontinuing use of rishuavastatin.
    in both patients, the use of reshvastatin and ARV-110 is required, given the significant increase in the plasma concentration of rishuavastatin at the same time as AST/ALT.
    , there are no other reports of related level 3/4 adverse events (AEs).
    15 patients received a PSA response assessment (excluding 1 patient who stopped treatment due to disease progression and 2 patients who had just started treatment).
    8 of them took an initial dose of 140 mg.
    2 patients in the 140 mg dose group, who had previously received encoryluamine and abitron, chemotherapy, bicaruamine and radon 223, as well as other treatment options, were shown to have decreased PSA by more than 50%.
    one of the patients developed two AR mutations known to cause enhelyulamine resistance.
    another patient also received an unconfirmed partial RECIST response (confirmation trial pending).
    the trial of patients receiving longer cycles (8 weeks and more) at the time of the data cut-off is still ongoing.
    the latest clinical trial data available now show that the ARV-110 is acceptable lying safe.
    maximum tolerable dose (MTD) has not yet been established and the determination of the recommended dose (RP2D) in stage 2 continues in the trial.
    in addition, ARV-110 has shown antitumor activity in patients treated with enmesylua/abitron, with PSA responses confirmed in 2 of the patients, one of which is associated with a decrease in tumors.
    Arvinas, a clinical-phasebiotic company, is dedicated to improving the lives of patients with debilitating and life-threatening diseases by identifying, developing and commercializing therapies that degrade pathogenic proteins.
    Arvinas uses its proprietary technology platform to design a project for clyin or PROTAC-targeted protein degradation agents designed to effectively degrade and remove disease-causing proteins using the body's own natural protein treatment system.
    Arvinas currently has two clinical trials under way in the field of oncology: ARV-110 for the treatment of metastatic derebelctprostate prostate cancer patients and ARV-471 for the treatment of patients with ER -HER2-local advanced or metastatic breast cancer.
    in addition, the company's next generation of androgen receptors and estrogen receptor degradation agents are being developed.
    , of course, they chose the field of neuroscience outside oncology as their second-largest focus, and there are currently two targets in the field: tau protein (treatment for Alzheimer's disease) and alpha-synaptic nuclein (treatment of Parkinson's).
    they have also shown that PROTAC drugs, which are slightly larger than traditional small molecule drugs, are more likely to penetrate the blood-brain barrier.
    Arvinas spent $45.2 million on research and development in 2018, increased its annual research and development cost to $67.2 million in 2019, and $21.7 million in the first quarter of 2020, primarily for the clinical development of the androgen receptor (AR) degradation agent ARV-110 and estrogen receptor (ER) degradation agent ARV-827.
    Figure 4: Arvinas research and development pipeline.
    from Reference 2Arvinas Financing and Research and Development Partnership from 2013 to April 2018, Arvinas completed a total of more than $100 million in financing, supported by a number of pharmaceutical investors.
    on September 29, 2018, Arvinas went public on NASDAQ, raising $120 million.
    in addition, Merck's $430 million, Genentech's 650 million, Pfizer's $8.3 billion and Bayer's $110 million- and big-money-steaming-a-Lago-a-lago-a-lago-a-company has partnered to develop protein degradation therapy.
    also involved other PROTAC start-ups (Kymera Therapeutics Kymera, C4 Therapeutics, Vividion, Nurix, etc.), while domestic Sequoia Capital, Minand Capital, Hongyu Capital, Tong tong and Stake are also involved.
    Figure 5: Arvinas's financing history.
    from reference 6 domestic PROTAC layout proTAC first echelon company mainly lingke pharmaceutical, Di Technology, Suzhou pioneering pharmaceutical industry and five-yuan biology.
    Lingke Pharmaceuticals is founded by Dr. Wan Zhaokui, former head of research and development chemistry and related sciences in The Pacific region of Johnson and Johnson, Wang Jun, former vice president of biology at an internationally renowned biopharmaceutical company, Michael Vazquez, former director of pharmaceutical chemistry at an internationally renowned pharmaceutical company, and Chen Wei, former investment partner of Changjiang Capital Biopharmaceutical Fund.
    focus on cancer, immunity, inflammation and other diseaseareas.
    April 17, 2020, Lingke Pharmaceuticals received tens of millions of yuan in Round A financing.
    November 15, 2018, Lingke Pharmaceuticals (Hangzhou) won the first prize for its "non-drugable" protein target project at the 7th China Innovation and Entrepreneurship Competition's Biopharmaceutical Industry Finals challenge "Non-Drug" Protein Target Project.
    the company's PROTAC research and development pipeline is still in the drug discovery stage and has not yet been declared.
    Chengdu Tidi Technology Chengdu Di Technology is mainly committed to the field of protein degradation new drug development, founded in 2014, located in Chengdu, China.
    , Tidi Technologies has established a proprietary protein degradation new drug development platform and developed unique PRODED (Protein Degradation Drug) technology.
    is now mainly in cooperation with Sun Yat-sen University Affiliated Oncology Hospital to develop a new PROTAC drug that targets the degradation of Smad3 protein and the use of PRODED platform to develop anti-coronary virus seed compounds based on protein degradation mechanism, the structure has not been announced.
    , proTAC drugs that have not yet been clinically declared are in the early screening stage.
    Suzhou Pioneering Pharmaceuticals Suzhou Development Pharmaceutical Co., Ltd. was founded in 2009 by Dr. Tong You, a former vice president of Angion Pharmaceutical Research Co., Ltd. in the United States.
    mainly layouts a diversified product pipeline with small molecule innovative drugs, bio-innovative drugs and combination therapies.
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