Retinal pigment epithelial cells (RPECs) are a type of retinal cells that structurally and physiologically support photoreceptors. However, hyperglycemia has been shown to play a critical role in the progression of diabetic retinopathy (DR), which is one of the leading causes of vision impairment. In the diabetic eye, the high glucose environment damages RPECs via the induction of oxidative stress, leading to the release of excess reactive oxygen species (ROS) and triggering apoptosis. In this study, we aim to investigate the antioxidant mechanism of Vitamin C in reducing hyperglycemia-induced stress and whether this mechanism can preserve the function of RPECs.

METHODS AND RESULTS:

ARPE-19 cells were treated with high glucose in the presence or absence of Vitamin C. Cell viability was measured by MTT assay. Cleaved poly ADP-ribose polymerase (PARP) was used to identify apoptosis in the cells. ROS were detected by the DCFH-DA reaction. The accumulation of sorbitol in the aldose reductase (AR) polyol pathway was determined using the sorbitol detection assay. Primary mouse RPECs were isolated from adult mice and identified by Rpe65 expression. The mitochondrial damage was measured by mitochondrial membrane depolarization. Our results showed that high glucose conditions reduce cell viability in RPECs while Vitamin C can restore cell viability, compared to the vehicle treatment. We also demonstrated that Vitamin C reduces hyperglycemia-induced ROS production and prevents cell apoptosis in RPECs in an AR-independent pathway.

CONCLUSIONS:

These results suggest that Vitamin C is not only a nutritional necessity but also an adjuvant that can be combined with AR inhibitors for alleviating hyperglycemic stress in RPECs.

2024-11-04·INORGANIC CHEMISTRY

Azolato-Bridged Dinuclear Platinum(II) Complexes Exhibit Androgen Receptor-Mediated Anti-Prostate Cancer Activity

Article

作者: Matsunaga, Takeshi ; Uemura, Masako ; Komeda, Seiji ; Hirota, Yoshihisa ; Harusawa, Shinya ; Arai, Tasuku ; Yoneyama, Hiroki ; Morii, Magotoshi ; Oshima, Masashi ; Suhara, Yoshitomo ; Usami, Yoshihide ; Ashizawa, Taiki

Prostate cancer is an androgen-dependent malignancy that presents a marked treatment challenge, particularly after progression to the castration-resistant stage. Traditional treatments such as androgen deprivation therapy often lead to resistance, necessitating novel therapeutic approaches. Previous studies have indicated that some of the azolato-bridged dinuclear platinum(II) complexes (general formula: [{cis-Pt(NH₃)₂}₂(μ-OH)(μ-azolato)]X₂, where azolato = pyrazolato, 1,2,3-triazolato, or tetrazolato and X = nitrate or perchlorate) inhibit androgen receptor (AR) signaling. Therefore, here we investigated the potential of 14 such complexes as agents for the treatment of prostate cancer by examining their antiproliferative activity in the human prostate adenocarcinoma cell line LNCaP. Several of the complexes, particularly 5-H-Y ([{cis-Pt(NH₃)₂}₂(μ-OH)(μ-tetrazolato-N2,N3)](ClO₄)₂), effectively inhibited LNCaP cell growth, even at low concentrations, by direct modulation of AR signaling, and by binding to DNA and inducing apoptosis, which is a common mechanism of action of Pt-based drugs such as cisplatin (cis-diamminedichloridoplatinum(II)). Comparative analysis with cisplatin revealed superior inhibitory effects of these complexes. Further investigation revealed that 5-H-Y suppressed mRNA expression of genes downstream from AR and induced apoptosis, particularly in cells overexpressing AR, highlighting its potential as an AR antagonist. Thus, we provide here insights into the mechanisms underlying the antiproliferative effects of azolato-bridged complexes in prostate cancer.

2024-11-01·INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

Androgen receptor regulates the differentiation of myoblasts under cyclic mechanical stretch and its upstream and downstream signals

Article

作者: Hu, Jing ; Qian, Zhenyu ; Fu, Shaoting ; Wang, Gang ; Wang, Xiaohui

Our previous studies have demonstrated the important roles of androgen receptor (AR) in myoblast proliferation regulated by 15 % (mimic appropriate exercise) and 20 % (mimic excessive exercise) mechanical stretches. Except for myoblast proliferation, differentiation is also an important factor affecting muscle mass and strength. But the role of AR in stretch-regulated myoblast differentiation and AR's upstream and downstream signals remain unknown. In the present study, firstly the differences of myogenic differentiation between C2C12 (with AR expression) and L6 (without AR expression) myoblasts induced by 15 % and 20 % mechanical stretches were compared; secondly, AR antagonist flutamide and AR agonist GTx-007 were used in 15 % and 20 % stretched myoblasts respectively to confirm AR's roles in stretch-regulated myoblast differentiation; thirdly, RNA-seq, molecular dynamic simulation (MD) and co-immunoprecipitation were performed to screen the downstream and upstream molecules of AR during stretches. We found that (1) 15 % stretch increased while 20 % stretch decreased myotube number in differentiating C2C12 and L6 myoblasts, with more significant changes in C2C12 cells than L6 cells; (2) in stretched C2C12 myoblasts, AR antagonist flutamide inhibited 15 % stretch-promoted differentiation while AR agonist GTx-007 reversed 20 % stretch-inhibited differentiation (reflected by changes in myotube number, MHC contents of fast-twitch and slow-twitch fiber, and the levels of myogenic regulatory factors (MRFs) such as MyoD and myogenin); (3) KEGG analysis of RNA-seq showed that the differently expressed genes (DEGs) in C2C12 cells induced by 15 % stretch were enriched in FoxO and JAK-STAT signaling pathways, while DEGs by 20 % stretch were enriched in FoxO and MAPK signaling pathways; (4) MD and co-immunoprecipitation showed that β1 integrin could interact with AR and influence AR's activity in C2C12 cells. In conclusion, AR plays important roles in myoblast differentiation promoted by 15 % stretch while inhibited by 20 % stretch, which was fulfilled through FoxO-MRFs. In addition, α7β1 integrin may be a bridge linking mechanical stretch and AR. This study is beneficial to deeply understand the roles and mechanisms of AR in stretch-regulated muscle mass and strength; and reports firstly that myoblasts sense mechanical stimulus and transmit into intracellular AR via α7β1 integrin.

项与 AR Antagonist (Eikon Therapeutics) 相关的新闻（医药）

2024-05-06

·BioSpace

ORIC Pharmaceuticals Reports First Quarter 2024 Financial Results and Operational Updates

Initiated three ORIC-114 Phase 1b expansion cohorts in NSCLC patients with EGFR exon 20 insertion, HER2 exon 20 insertion, or EGFR atypical mutations; updated Phase 1b data expected in the first half of 2025 Presented initial ORIC-944 Phase 1b monotherapy data demonstrating potential best-in-class pro strong pharmacokinetic, pharmacodynamic, and safety results in patients with prostate cancer; proceeding into combination with AR inhibitor(s) in metastatic prostate cancer Presented updated ORIC-944 preclinical data at the 2024 AACR Annual Meeting highlighting superior drug properties and synergistic activity in combination with AR inhibitors in prostate cancer models Strengthened cash position with $125 million private placement financing in January 2024; cash and investments of $331.5 million expected to fund operating plan into late 2026 SOUTH SAN FRANCISCO and SAN DIEGO, May 06, 2024 (GLOBE NEWSWIRE) -- ORIC Pharmaceuticals, Inc., (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today reported financial results and operational updates for the quarter ended March 31, 2024. “In the first quarter of 2024, we continued making steady progress across our clinical and preclinical programs, while also strengthening our cash position and runway,” said Jacob M. Chacko, M.D., president and chief executive officer. “Most recently, we announced the selection of provisional recommended phase 2 doses for ORIC-114 that confirm its wide therapeutic index, and we initiated three expansion cohorts in patients with EGFR/HER2 mutated non-small cell lung cancer, including those with active, untreated CNS metastases. For ORIC-944, we presented clinical and preclinical data that further reinforce its promise as a potential best-in-class treatment option for prostate cancer based upon its superior drug properties and clinical half-life versus competitor PRC2 inhibitors. We are laser focused on flawless execution as we continue to advance these two programs towards the initiation of registrational studies, which we anticipate in the second half of 2025.” First Quarter 2024 and Other Recent Highlights ORIC-114: a brain penetrant, orally bioavailable, irreversible EGFR/HER2 inhibitor Announced the completion of the dose escalation portion of the Phase 1b trial of ORIC-114 and the selection of the provisional recommended phase 2 doses. Announced first patients dosed across three expansion cohorts in the Phase 1b trial of ORIC-114 in patients with mutated non-small cell lung cancer (NSCLC), including EGFR exon 20 insertion (EGFR exon 20 inhibitor naïve), HER2 exon 20 insertion, and EGFR atypical mutations. Initiated an extension cohort to evaluate ORIC-114 for the treatment of patients with first-line, treatment-naïve EGFR exon 20 insertion NSCLC. Expect to report updated Phase 1b data in the first half of 2025. ORIC-944: a potent and selective allosteric inhibitor of PRC2 Reported initial Phase 1b monotherapy data for ORIC-944 in metastatic prostate cancer supporting advancement into combination development and demonstrating the potential as a best-in-class PRC2 inhibitor, including a clinical half-life of ~20 hours, no signs of CYP autoinduction that was observed with first-generation PRC2 inhibitors, robust target engagement, and a well-tolerated safety profile. Presented preclinical data at the 2024 AACR Annual Meeting demonstrating superior preclinical drug properties and synergy data in prostate cancer models, reinforcing the promise of ORIC-944 as a potential best-in-class treatment for combination with AR inhibitors. Proceeding with combination of ORIC-944 with AR inhibitor(s) in metastatic prostate cancer and expect to provide a program update in mid-2024. ORIC-533: a highly potent, orally bioavailable small molecule inhibitor of CD73 The company is completing a Phase 1b trial and plans to pursue strategic partnership for combination studies. Discovery Pipeline: Presented at the 2024 AACR annual meeting the first preclinical data on ORIC-613, a potential first- and best-in-class development candidate selectively inhibiting PLK4. Corporate Highlights: Strengthened cash position and runway with a $125 million private placement financing from new and existing healthcare specialist funds in January 2024. First Quarter 2024 Financial Results Cash, Cash Equivalents and Investments: Cash, cash equivalents and investments totaled $331.5 million as of March 31, 2024, which the company expects will be sufficient to fund its operating plan into late 2026. R&D Expenses: Research and development (R&D) expenses were $22.0 million for the three months ended March 31, 2024, compared to $19.5 million for the three months ended March 31, 2023, an increase of $2.4 million. The increase was due to a net increase in external expenses related to the advancement of product candidates and discovery programs, as well as higher personnel costs, including additional non-cash stock-based compensation of $0.7 million. G&A Expenses: General and administrative (G&A) expenses were $7.0 million for the three months ended March 31, 2024, compared to $6.2 million for the three months ended March 31, 2023, an increase of $0.9 million. The increase was primarily due to higher personnel costs, including additional non-cash stock-based compensation of $0.7 million. About ORIC Pharmaceuticals, Inc. ORIC Pharmaceuticals is a clinical stage biopharmaceutical company dedicated to improving patients’ lives by Overcoming Resistance In Cancer. ORIC’s clinical stage product candidates include (1) ORIC-114, a brain penetrant inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations, being developed across multiple genetically defined cancers, (2) ORIC-944, an allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the EED subunit, being developed for prostate cancer, and (3) ORIC-533, an orally bioavailable small molecule inhibitor of CD73, a key node in the adenosine pathway believed to play a central role in resistance to chemotherapy- and immunotherapy-based treatment regimens, being developed for multiple myeloma. Beyond these three product candidates, ORIC is also developing multiple precision medicines targeting other hallmark cancer resistance mechanisms. ORIC has offices in South San Francisco and San Diego, California. For more information, please go to , and follow us on X or LinkedIn. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Statements in this press release that are not purely historical are forward-looking statements. Such forward-looking statements include, among other things, statements regarding the continued clinical development of ORIC-114 and ORIC-944; ORIC-114, ORIC-944 and ORIC-533 clinical outcomes, which may materially change as patient enrollment continues or more patient data become available; the development plans and timelines for ORIC-114, ORIC-944 and ORIC’s other product candidates; the potential advantages of ORIC-114, ORIC-944 and ORIC’s other product candidates and programs; plans underlying ORIC’s clinical trials and development; anticipated program milestones, including timing of program and data updates and the initiation of registrational studies; the period over which ORIC estimates its existing cash, cash equivalents and investments will be sufficient to fund its current operating plan; and statements by the company’s chief executive officer. Words such as “believes,” “anticipates,” “plans,” “expects,” “intends,” “will,” “goal,” “potential” and similar expressions are intended to identify forward-looking statements. The forward-looking statements contained herein are based upon ORIC’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those projected in any forward-looking statements due to numerous risks and uncertainties, including but not limited to: risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics and operating as an early clinical stage company; ORIC’s ability to develop, initiate or complete preclinical studies and clinical trials for, obtain approvals for and commercialize any of its product candidates; changes in ORIC’s plans to develop and commercialize its product candidates; the potential for clinical trials of ORIC’s product candidates to differ from preclinical, initial, interim, preliminary or expected results; negative impacts of health emergencies, economic instability or international conflicts on ORIC’s operations, including clinical trials; the risk of the occurrence of any event, change or other circumstance that could give rise to the termination of ORIC’s license and collaboration agreements; the potential market for ORIC’s product candidates, and the progress and success of competing therapeutics currently available or in development; ORIC’s ability to raise any additional funding it will need to continue to pursue its business and product development plans; regulatory developments in the United States and foreign countries; ORIC’s reliance on third parties, including contract manufacturers and contract research organizations; ORIC’s ability to obtain and maintain intellectual property protection for its product candidates; the loss of key scientific or management personnel; competition in the industry in which ORIC operates; general economic and market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section titled “Risk Factors” in ORIC’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (the “SEC”) on May 6, 2024, and ORIC’s future reports to be filed with the SEC. These forward-looking statements are made as of the date of this press release, and ORIC assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Contact: Dominic Piscitelli, Chief Financial Officer dominic.piscitelli@oricpharma.com info@oricpharma.com ORIC PHARMACEUTICALS, INC. CONDENSED BALANCE SHEETS (in thousands, except share and per share amounts) March 31, 2024 December 31, 2023 (unaudited) Assets Current assets: Cash, cash equivalents and short-term investments $ 316,778 $ 208,187 Prepaid expenses and other current assets 7,305 4,410 Total current assets 324,083 212,597 Long-term investments 14,694 26,852 Property and equipment, net 2,801 2,862 Other assets 9,208 9,696 Total assets $ 350,786 $ 252,007 Liabilities and Stockholders' Equity Current liabilities: Accounts payable $ 2,988 $ 944 Accrued liabilities 12,222 19,514 Total current liabilities 15,210 20,458 Other long-term liabilities 6,931 7,461 Total liabilities 22,141 27,919 Total stockholders' equity 328,645 224,088 Total liabilities and stockholders' equity $ 350,786 $ 252,007 ORIC PHARMACEUTICALS, INC. STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (Unaudited) (in thousands, except share and per share amounts) Three Months Ended March 31, 2024 2023 Operating expenses: Research and development $ 21,960 $ 19,516 General and administrative 7,030 6,162 Total operating expenses 28,990 25,678 Loss from operations (28,990 ) (25,678 ) Other income, net 3,979 1,733 Net loss $ (25,011 ) $ (23,945 ) Other comprehensive (loss) income: Unrealized (loss) gain on investments (420 ) 792 Comprehensive loss $ (25,431 ) $ (23,153 ) Net loss per share, basic and diluted $ (0.37 ) $ (0.53 ) Weighted-average shares outstanding, basic and diluted 67,349,551 45,090,166

临床1期财报AACR会议

100 项与 AR Antagonist (Eikon Therapeutics) 相关的药物交易

登录后查看更多信息