YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacy.

Article

作者: Liu, Shwu-Huey ; Cai, Wei ; Arammash, Mohammad ; Cheng, Peikwen ; Cheng, Yung-Chi ; Lam, Wing ; Guan, Fulan ; Jiang, Zaoli

Introduction: Prostate cancer is the second leading cause of cancer death among men in the United States. Castration-Resistant Prostate Cancer (CRPC) often develops resistance to androgen deprivation therapy. Resistance in CRPC is often driven by AR variants and glucocorticoid receptor (GR). Thus, drugs that target both could be vital in overcoming resistance. Methods: Utilizing the STAR Drug Discovery Platform, three hundred medicinal plant extracts were examined across 25 signaling pathways to identify potential drug candidates. Effects of the botanical drug YIV-818-A, derived from optimized water extracts of Rubia cordifolia (R.C.), on Dihydrotestosterone (DHT) or Dexamethasone (DEX) induced luciferase activity were assessed in 22RV1 cells harboring the ARE luciferase reporter. Furthermore, the key active compounds in YIV-818-A were identified through activity guided purification. The inhibitory effects of YIV-818-A, RA-V, and RA-VII on AR and GR activities, their impact on AR target genes, and their roles in modifying epigenetic status were investigated. Finally, the synergistic effects of these compounds with established CRPC drugs were evaluated both in vitro and in vivo. Results: YIV-818-A was found to effectively inhibit DHT or DEX induced luciferase activity in 22RV1 cells. Deoxybouvardin (RA-V) was identified as the key active compound responsible for inhibiting AR and GR activities. Both YIV-818-A and RA-V, along with RA-VII, effectively downregulated AR and AR-V proteins through inhibiting protein synthesis, impacted the expression of AR target genes, and modified the epigenetic status by reducing levels of Bromodomain and Extra-Terminal proteins (Brd2/Brd4) and H3K27Ac. Furthermore, these compounds exhibited synergistic effects with apalutamide, darolutamide, or enzalutamide, and suppressed AR mediated luciferase activity of 22RV1 cells. Co-administration of YIV-818-A and enzalutamide led to a significant reduction of 22RV1 tumor growth in vivo. Different sources of R.C. had variable levels of RA-V, correlating with their potency in AR inhibition. Discussion: YIV-818-A, RA-V, and RA-VII show considerable promise in addressing drug resistance in CRPC by targeting both AR protein and GR function, along with modulation of vital epigenetic markers. Given the established safety profile of YIV-818-A, these findings suggest its potential as a chemopreventive agent and a robust anti-prostate cancer drug.

项与 YIV-818-A 相关的新闻（医药）

2024-02-05

·GlobeNewswire-Health Care

Yiviva Announces Memorandum of Understanding with AstraZeneca to Develop Platforms, Technologies, and Innovative Therapeutics through a Systems Biology Approach

NEW YORK and SHANGHAI, China, Feb. 05, 2024 (GLOBE NEWSWIRE) -- Yiviva, a clinical-stage, platform biotechnology company developing systems biology medicines to treat aging-related diseases, signed a memorandum of understanding (MOU) with AstraZeneca China to establish a research and development collaboration at AstraZeneca’s Innovation Campus (iCampus) in Chengdu, China. The signing ceremony took place at the 2023 China International Import Expo (CIIE) at the National Exhibition and Convention Center in Shanghai. To address global unmet medical needs, Together Yiviva and AstraZeneca China will jointly build platforms for scientific research transformation and industrial development led by academicians and experts with the aim to modernize botanical medicines in accordance with new regulatory pathways for botanical medicines by the United States Food and Drug Administration (FDA) and China National Medical Products Administration (NMPA). “2023 marks the 30th anniversary of AstraZeneca in China. In collaboration with the Chengdu government and Chengdu High-Tech Industrial Zone (CDHT), AstraZeneca is establishing a modern healthcare development platform integrating traditional Chinese medicine and Western medicine. At CIIE, AstraZeneca announced plans to further globalize Chinese medicine. Our strategic partnership with Yiviva, will advance our blueprint for how to develop innovative medicines inspired by Chinese medicine,” remarked Lily Zhu, Vice President of AstraZeneca China and Head of DCI and CSE. “Disease knows no borders. By bringing together the knowledge and best practices of Western and Eastern Medicine, WE Medicine, we can learn from ancient wisdom to develop future medicines. Together with AstraZeneca China’s expertise, ecosystem, and resources, and Yiviva’s team, platform technologies, and pipeline, we can pioneer a new paradigm for systems biology drug development to address global unmet medical needs,” said Peikwen Cheng, Co-Founder and CEO of Yiviva. About Yiviva’s Platforms and Pipeline in Oncology Yiviva’s STAR (signal transduction, activity and response) drug discovery platform accelerates the identification of botanical therapeutics that influence immune function, inflammatory responses, cell growth, metabolic functions, and hormone activity. Through STAR, Yiviva can design sophisticated multi-target drugs that map to complicated disease biology. Yiviva has discovered six first-in-class drug candidates to treat cancer and inflammatory diseases. Yiviva applies patented, mechanism-based quality control linked to biological activity to manufacture batch-to-batch consistent drug product that satisfies established regulatory requirements for complex products. Yiviva’s lead candidate drug YIV-906 is a proprietary extract of 4 medicinal plants, inspired by an 1800-year-old traditional Chinese medicine formula. YIV-906 acts as an immunomodulator in the tumor microenvironment, turning cold tumors hot and potentiating anti-tumor activity for chemotherapies, immunotherapies, cell therapies, or radiation therapies; and acts as a cytoprotector in the gastrointestinal tract, reducing non-hematological toxicities and speeding up damaged tissue recovery. Yiviva has conducted 8 early-stage clinical trials in solid tumors (hepatocellular carcinoma, pancreatic cancer, colorectal cancer, and rectal cancers), with promising data suggesting that YIV-906 could prolong survival and improve quality of life. Yiviva recently recruited its last-patient-in in a first-line, randomized, double-blinded Phase 2b study of sorafenib plus YIV-906 in the treatment of hepatocellular carcinoma patients with hepatitis B. The CALM study is a multi-regional trial in the United States, Mainland China, Hong Kong, and Taiwan and expects a data readout in 2024. Yiviva recently published preclinical data conducted at Yale University about its novel therapeutic YIV-818-A to treat prostate cancer. YIV-818-A acts through multiple mechanisms, including androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation and could help overcome drug resistance to prostate cancer and could enhance apalutamide, darolutamide, or enzalutamide efficacy. About Yiviva Yiviva is a clinical stage, platform biotechnology company developing systems biology medicines to prevent, treat, and/or cure aging-related diseases, including cancer and inflammatory diseases. The company was launched with Yale University and Henry Bronson Professor of Pharmacology and Medicine Yung-Chi Cheng as co-founders, with teams in the United States and Greater China. Yiviva’s investors include the National Foundation for Cancer Research and the Asian Fund for Cancer Research. For further information, please visit https://yiviva.com. About AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca. Contact:Email: hello@yiviva.com A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/8d78fdf0-e819-4a98-abe1-3944978b9ad8

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