This phase I trial tests the safety, side effects, and best dose of pidnarulex (CX-5461) in treating patients with solid tumors that has spread from where it first started (primary site) to other places in the body (metastatic). Pidnarulex is an oral inhibitor of ribonucleic acid (RNA) polymerase I (Pol I), with potential antineoplastic activity. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill cancer cells. Giving pidnarulex may be safe, tolerable and/or effective in treating patients with metastatic solid tumors.

开始日期2024-12-16

申办/合作机构

National Cancer Institute

NCT05425862 / Suspended临床1期IIT

Phase 1 Trial of Pidnarulex and Talazoparib in Patients With Metastatic Castration Resistant Prostate Cancer

This is phase I, open label, multicentre, dose-escalation study where both doses of talazoparib and pidnarulex will be escalated to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for the combination. It is possible that either 1 or 2 RP2D of the combination will be defined at the end of the study. Patients with disease that is deemed to be amendable to repeated tumour biopsies will be invited to undergo optional paired biopsies: at baseline and Cycle 1 Day 9 + 3 days and at the time of progression. Pidnarulex will be given as an IV infusion on days 1 and 8 of a 28 day cycle and talazoparib will be taken once daily continuously. Disease status will be assessed at regular intervals by CT scans, radionuclide bone scans, and PSA. Throughout the study, safety and tolerability will be assessed and established procedures for management of toxicities will be applied

开始日期2022-10-21

申办/合作机构

Peter MacCallum Cancer Institute

NCT04890613 / Recruiting临床1期

Phase Ib Expansion Study of CX-5461 in Patients With Solid Tumours and BRCA2 and/or PALB2 Mutation

This is an open-label, multi-center, phase 1b study designed to determine a tolerable dose of CX-5461 administered by IV infusion on Day 1 and Day 8 of a 28-day cycle in patients with selected solid tumours and associated mutations for future Phase II trials. The safety and tolerability of CX-5461, preliminary evidence of antitumor effect and the effect of CX-5461 on the Health-Related Quality of Life (HRQoL) will also be evaluated. The study will also evaluate the predictive value of mutational signatures and explore the significance of dynamic changes in ctDNA levels and plasma DNA methylome profiling in this study's exploratory cohort.

开始日期2021-09-08

申办/合作机构

生华生物科技股份有限公司

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100 项与 Pidnarulex 相关的专利（医药）

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134

项与 Pidnarulex 相关的文献（医药）

2024-10-01·FREE RADICAL BIOLOGY AND MEDICINE

CX-5461 ameliorates disease in lupus-prone mice by triggering B-cell ferroptosis via p53-SLC7A11-ALOX12 pathway

Article

作者: Zhang, Yongqiang ; Liu, Shanshan ; Sun, Lingyun ; Wen, Xin ; Guo, Panpan ; Zhu, Huiming ; Tsai, Hsiang-I ; Zhang, Zhengyang ; Wang, Dandan ; Wu, Yingyi ; Zhang, Zining

CX-5461, a first-in-class compound, is widely recognized as a selective inhibitor of RNA polymerase I. Recently, it has been reported to possess novel immunosuppressive properties with significant therapeutic effects in transplantation immune rejection. However, the potential use of CX-5461 for Systemic Lupus Erythematosus (SLE) treatment remains unknown. In this study, we elucidated the mechanism underlying the therapeutic efficacy of CX-5461 in lupus. Our findings demonstrated that CX-5461 selectively targets B cells and effectively reduces the proportions of B cells, germinal center B cells, and plasma cells in MRL/MPJ-Fas^lpr and Resiquimod (R848)-induced lupus mice. Molecular studies revealed that CX-5461 modulates CD36-Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4)-mediated glycerolipid metabolism in B cells, triggering ferroptosis through the p53- Solute Carrier Family 7 Member 11 (SLC7A11)- Arachidonate 12-Lipoxygenase (ALOX12) pathway, thereby decreasing IgG and Anti-Double-Stranded Deoxyribonucleic Acid (dsDNA) antibody levels and attenuating lupus. Collectively, these results suggest that CX-5461 holds promise as an effective candidate for targeted therapy against lupus.

2024-10-01·JOURNAL OF BIOLOGICAL CHEMISTRY

The Unique Pt(II)-Induced Nucleolar Stress Response and its Deviation from DNA Damage Response Pathways

Article

作者: Pigg, Hannah C ; Moon, Caleb H. ; Griffin, Christopher R ; Alley, Katelyn R. ; Griffin, Christopher R. ; Moon, Caleb H ; Pigg, Hannah C. ; Kraske, Sarah J. ; DeRose, Victoria J. ; Kraske, Sarah J ; DeRose, Victoria J ; Alley, Katelyn R

The mechanisms of action for the platinum compounds cisplatin and oxaliplatin have yet to be fully elucidated, despite the worldwide use of these drugs. Recent studies suggest that the two compounds may be working through different mechanisms, with cisplatin inducing cell death via the DNA damage response (DDR) and oxaliplatin utilizing a nucleolar stress-based cell death pathway. While cisplatin-induced DDR has been subject to much research, the mechanisms for oxaliplatin's influence on the nucleolus are not well understood. Prior work has outlined structural parameters for Pt(II) derivatives capable of nucleolar stress induction. In this work, we gain insight into the nucleolar stress response induced by these Pt(II) derivatives by investigating potential correlations between this unique pathway and DDR. Key findings from this study indicate that Pt(II)-induced nucleolar stress occurs when DDR is inhibited and works independently of the ATM/ATR-dependent DDR pathway. We also determine that Pt(II)-induced stress may be linked to the G₁ cell cycle phase, as cisplatin can induce nucleolar stress when cell cycle inhibition occurs at the G₁/S checkpoint. Finally, we compare Pt(II)-induced nucleolar stress with other small-molecule nucleolar stress-inducing compounds Actinomycin D, BMH-21, and CX-5461, and find that only Pt(II) compounds cause irreversible nucleolar stress. Taken together, these findings contribute to a better understanding of Pt(II)-induced nucleolar stress, its deviation from ATM/ATR-dependent DDR, and the possible influence of cell cycle on the ability of Pt(II) compounds to cause nucleolar stress.

2024-09-01·Heliyon

Molecular basis of CX-5461-induced DNA damage response in primary vascular smooth muscle cells

Article

作者: Guo, Xiaosun ; Chen, Ye ; Wang, Jianli ; Jiang, Fan ; Liu, Huiqing ; Liu, Tengfei ; Wang, Xiaoyun ; Zhang, Jing ; Pan, Guopin ; Cui, Xiaopei

Our previous studies have shown that the novel selective RNA polymerase I inhibitor CX-5461 suppresses proliferation of vascular smooth muscle cells, mainly by inducing DNA damage response (DDR), including activations of ataxia telangiectasia mutated (ATM)/ATM and Rad3-related (ATR) and p53. Currently, there is no information about the molecular mechanism(s) underlying CX-5461-induced DDR in vascular cells, while the results obtained in cancer cells and immortalized cell lines are controversial. In this study, we examined the responses of various DDR pathways to CX-5461 treatment in primary aortic smooth muscle cells isolated from normal adult Sprague Dawley rats. We demonstrated that CX-5461-induced DDR was not associated with activations of the nucleotide excision repair, DNA mismatch repair, or the non-homologous end joining pathways, while the homologous recombination pathway was activated. However, the alkaline comet assay did not show massive DNA double strand breaks in CX-5461-treated cells. Instead, CX-5461-induced DDR appeared to be related to induction of DNA replication stress, which was not attributable to increased formation of G-quadruplex or R-loop structures, but might be explained by the increased replication-transcription conflict. CX-5461-induced DDR was not exclusively confined to rDNA within the nucleolar compartment; the extra-nucleolar DDR might represent a distinct secondary response related to the downregulated Rad51 expression in CX-5461-treated cells. In summary, we suggest that DNA replication stress may be the primary molecular event leading to downstream ATM/ATR and p53 activations in CX-5461-treated vascular smooth muscle cells. Our results provide further insights into the molecular basis of the beneficial effects of CX-5461 in proliferative vascular diseases.

项与 Pidnarulex 相关的新闻（医药）

2024-11-02

·今日头条

有效抑制体内肿瘤生长！复旦大学/南昌大学合作发文：有前景的癌症靶向治疗新策略

【导读】升高的核糖体生物发生与癌症的快速生长和进展相关。靶向阻断核糖体生物发生可诱导核仁应激，从而优先导致恶性细胞的清除。 10月30日，复旦大学/南昌大学研究人员合作共同在期刊《Advanced Science》上发表了研究论文，题为“Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression”，在本研究中，研究人员发现核仁蛋白BRIX1是核糖体生物发生和p53激活之间稳态的关键调节因子。BRIX1通过损害MDM2和核糖体蛋白RPL5和RPL11之间的相互作用来阻止p53在核仁应激反应中的活化，从而触发癌细胞对化疗的耐药性。相反，BRIX1的缺失诱导核仁应激，进而通过RPL5和RPL11激活p53，从而抑制肿瘤的生长。此外，工程化外泌体被开发，其表面装饰有iRGD，并负载BRIX1特异性siRNAs，用于治疗癌症。iRGD-Exo-siBRIX1在体内显著抑制结直肠癌的生长，增强5-FU化疗的疗效。总之，该研究揭示了BRIX1作为一种癌蛋白促进rRNA合成并抑制p53活性，同时也表明通过工程外泌体靶向抑制BRIX1可能是一种有效的癌症治疗方法。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202407370 背景信息 01 核糖体的生物发生是一个多步骤的过程，包括三个基本步骤：核糖体RNA （rRNA）和核糖体蛋白（RPs）的协调表达、rRNA前体的加工以及核糖体40S和60S亚基在核仁中的组装。核仁大小和数量的异常增加被认为是恶性细胞的重要标志，与癌症患者的不良预后相关。这是因为癌细胞需要以比正常细胞更高的速率产生核糖体，以满足其快速生长和增殖过程中蛋白质合成的需求。各种致癌信号已被发现通过增加核糖体的产生来促进癌症的生长。例如，c-Myc促进所有三种类型的rrna和参与核糖体生物发生的必需因子的合成。因此，靶向核仁功能有望成为根除癌细胞的有效方法，同时最大限度地减少对正常细胞的细胞毒性作用。有充分的证据表明，干扰核糖体生物发生的任何关键步骤都可能导致核仁应激，也称为核糖体应激。研究表明，RPL5、RPL11和RPS14等几种RPs可激活p53同源物TAp73，并在核仁应激时使癌蛋白c-Myc失活。多种策略已被证明可触发核仁应激。例如，多种化疗药物可诱导核糖体DNA （ribosome DNA, rDNA）损伤或阻碍前体rRNA加工，从而损害核糖体生物发生。一些化合物被开发出来通过抑制RNA聚合酶（Pol） I的活性来限制rRNA的合成，例如CX-5461和BMH-21。然而，后来发现这些药物也引起DNA损伤或染色质损伤。值得注意的是，在实验室环境中，研究表明，去除某些RPs或核仁蛋白对前rRNA加工至关重要，从而特异性地诱导核仁应激。这些发现促使研究人员进一步研究作为癌症治疗策略的触发核仁应激的潜力。 BRIX1缺乏通过激活核仁应激-p53通路抑制癌细胞的生长 02 由于BRIX1对于32S前rrna的处理是必需的，研究人员通过对核仁标记物NPM1进行免疫荧光（if）染色来测试BRIX1敲除是否可以触发核仁应激。正如预期的那样，敲低BRIX1导致NPM1从核仁迁移到核质，表明BRIX1缺乏导致核仁应激。众所周知，核仁应激时p53的激活需要RPL5/RPL11与MDM2的相互作用以及随之而来的MDM2的抑制。表达不能与RPL5和RPL11结合的MDM2突变体的癌细胞对核仁应激诱导的p53激活具有抗性，这一事实也证明了这一点。然后，研究人员阐明了敲低BRIX1是否通过RPL5和RPL11激活p53通路。结果表明，在CAL-51细胞和HCT116 p53+/+细胞中，去除RPL5或RPL11完全消除了BRIX1缺陷引起的p53活化。研究人员注意到，敲低BRIX1适度降低了RPL5和RPL11的水平，这可能是由于如前所述，核糖体成分可以相互稳定。此外，研究人员通过co-IP检测了BRIX1缺失是否增强了MDM2与RPL5或RPL11的相互作用。在正常生长条件下，MDM2可以与RPL5和RPL11轻度结合，而敲低BRIX1可以显著增加MDM2与这两种RPs的结合。MDM2与RPs之间的相互作用增加可能削弱MDM2对p53的E3连接酶活性。因此，研究人员进行了体内泛素化实验，以检测BRIX1缺陷是否影响mdm2介导的p53泛素化。结果表明，过表达MDM2促进p53的泛素化，而敲低BRIX1降低了MDM2引起的p53泛素化。敲除BRIX1显著延长了p53蛋白的半衰期。这些结果表明BRIX1缺陷触发核仁应激，导致RPL5/RPL11和MDM2之间的相互作用增加，最终导致p53的激活。敲除BRIX1可以激活核仁应力-p53通路，从而抑制肿瘤的生长接下来，研究人员通过敲低BRIX1的表达来研究BRIX1在携带野生型p53的癌细胞中的作用。结果表明，敲低BRIX1显著抑制CAL-51和MCF-7细胞的增殖和克隆形成。同样，敲除BRIX1可诱导g1期细胞周期阻滞和细胞凋亡。此外，通过敲除BRIX1，癌细胞的迁移也被显著抑制。综上所述，研究结果表明，BRIX1的缺失激活核仁应激-p53通路，从而抑制癌细胞的生长和增殖。结论 03 总之，本研究确定BRIX1是一种在结直肠癌和乳腺癌中过表达的癌蛋白，与不良预后相关。BRIX1通过与PeBoW复合物相互作用促进前rRNA的加工，并通过隔离RPL5和RPL11来抑制p53活性。相反，BRIX1的缺失激活p53，通过触发核仁应激来抑制癌症的生长。最后，研究结果表明，利用负载BRIX1特异性siRNA的外泌体递送系统可能是一种有前景的癌症治疗方法。【参考资料】 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202407370 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会 🕓 上海｜11月21日-24日 ▶ 第七届上海国际肿瘤内科学论坛 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛点击对应文字查看详情

临床申请siRNA临床1期信使RNA

2024-10-14

·PRNewswire

US FDA issues Study May Proceed letter for the Pilot Study of Pidnarulex Pharmacodynamics in Patients with Advanced Solid Tumors, Sponsored by the US National Cancer Institute

TAIPEI and SAN DIEGO, Oct. 14, 2024 /PRNewswire/ -- Senhwa Biosciences, Inc. (TPEx: 6492), a drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, today announced that FDA issues Study May Proceed letter for its developing drug Pidnarulex (CX-5461) in trial entitled "Pilot Study of Pidnarulex Pharmacodynamics in Patients with Advanced Solid Tumors" sponsored by the US National Cancer Institute (NCI). The study will assess whether Pidnarulex (CX-5461) induces a Rad51 response, in patients with and without homologous repair deficiency (HRD) genetic mutations. This pilot study also aims to explore potential biomarkers beyond BRCA1/2 and PALB2 that may demonstrate synthetic lethality with Pidnarulex (CX-5461). The findings from this study may identify patients who are more responsive to Pidnarulex (CX-5461) treatment, potentially expanding its therapeutic applications, and may accelerate its path to market approval. In addition to this monotherapy trial, the NCI is considering future clinical trials involving Pidnarulex (CX-5461) in combination with other therapies, such as immunotherapies and antibody-drug conjugates (ADCs). Should these trials proceed as planned, they will be led by the NCI, utilizing its vast medical expertise, scientific resources, and regulatory experience—support that could significantly accelerate the development of Pidnarulex. Pidnarulex (CX-5461), developed by Senhwa, is a first-in-class small-molecule designed to stabilize G-quadruplex (G4) structures, which are frequently observed in promoters of oncogenes. By stalling replication fork progression, Pidnarulex induces DNA damage and promotes cancer cell death. Through this mechanism, Pidnarulex holds great potential as a therapeutic agent for various cancers. In recent years, immunotherapy has been the fastest-growing category in the cancer drug market. According to the 2023 global best-selling drug market analysis, the first PD-1 inhibitor Keytruda(Pembrolizumab), developed by Merck, topped the sales charts with $25.11 billion. Immunotherapy and cancer drugs account for nearly half of the market sales. International clinical research indicates that combined immunotherapy can enhance tumor response rates, reduce mortality, and prolong patient survival. Given that only 20% to 25% of patients benefit from effective immunotherapy, Senhwa expects that in future immuno-combination therapy trials, CX-5461 will change the tumor microenvironment with its innovative mechanism, thereby enhancing the efficacy of immunotherapy, realizing the corporate mission of bringing hope to life. SOURCE Senhwa Biosciences, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法临床研究

2024-09-18

·PRNewswire

Senhwa Biosciences Announces IND Submission to US FDA for Pilot Study of Pidnarulex Pharmacodynamics in Patients with Advanced Solid Tumors sponsored by NCI

TAIPEI and SAN DIEGO, Sept. 17, 2024 /PRNewswire/ -- Senhwa Biosciences, Inc. (TPEx: 6492), , a drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, today announced that an Investigational New Drug (IND) application for Pidnarulex has been submitted to the U.S. FDA by the NCI. Senhwa' investigational drug, Pidnarulex (CX-5461), has been selected as an experimental drug in the NExT (NCI Experimental Therapeutics) cancer program, sponsored by the Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI), part of the U.S. National Institutes of Health (NIH), for a five-year period. This drug will be used in a pharmacodynamic (PD) pilot study involving patients with advanced solid tumors. In addition to this monotherapy trial, NCI is considering to plan future clinical trials for Pidnarulex (CX-5461) in combination with other therapies, including immunotherapy, antibody-drug conjugates (ADC), and PARP inhibitors (Poly ADP-ribose Polymerase inhibitors, PARPi). Should these trials be realized, they will be led by the NCI, leveraging its medical team, scientific talent network, and regulatory resources—capabilities that most biotech companies would struggle to accomplish independently. This support from the NCI is hoped to significantly accelerate the development and expansion of indications for Pidnarulex (CX-5461), ultimately benefiting patients with an earlier market launch. This clinical trial, for which the IND application has been submitted by NCI's Division of Cancer Treatment and Diagnosis (DCTD), aims to explore the response of various biomarkers to Pidnarulex (CX-5461) in patients with or without homologous recombination deficiency (HRD). Pidnarulex (CX-5461), developed by Senhwa, is a first-in-class small-molecule designed to stabilize G-quadruplex (G4) structures, which are frequently observed in promoters of oncogenes. By stalling replication fork progression, Pidnarulex induces DNA damage and promotes cancer cell death. Through this mechanism, Pidnarulex holds great potential as a therapeutic agent for various cancers. In recent years, immunotherapy has become the fastest-growing category in the cancer drug market, while the development of antibody-drug conjugates (ADC) is undoubtedly an important trend in biopharmaceuticals. Major pharmaceutical companies, including Pfizer, AbbVie, AstraZeneca, and Merck, have invested billions of dollars in acquiring or licensing related technologies. According to a recent report from market research firm Evaluate, the ADC market is expected to reach $30 billion by 2028, while the global cancer immunotherapy market will surpass a staggering $224 billion by 2030. Given that only about 20% to 25% of patients are effectively treated with immunotherapy, combining immunotherapy with targeted drugs is becoming increasingly important in cancer treatment. Combination therapies can address multiple treatment pathways within the complex tumor microenvironment and may enhance the efficacy of immunotherapy, making it a hot research area for major pharmaceutical companies. Therefore, Senhwa is confident and optimistic about the NCI's plans to advance clinical trials of Pidnarulex (CX-5461) in combination with immunotherapy and ADCs. SOURCE Senhwa Biosciences, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法临床申请抗体药物偶联物

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适应症	最高研发状态	国家/地区	公司	日期
血液肿瘤	临床2期	澳大利亚	-	2021-01-12
卵巢癌	临床2期	美国	生华生物科技股份有限公司	2021-01-10
乳腺癌	临床2期	加拿大	生华生物科技股份有限公司	2018-09-07
前列腺癌	临床1期	美国	生华生物科技股份有限公司	2022-10-31
晚期恶性实体瘤	临床1期	美国	生华生物科技股份有限公司	2021-09-08
晚期恶性实体瘤	临床1期	加拿大	生华生物科技股份有限公司	2021-09-08

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04890613 (Phase Ib expansion study of CX-5461, ESMO2024)	临床1期	晚期恶性实体瘤 BRCA2 \| PALB2 \| BRCA1 ... 更多	28	CX-5461 250 mg/m2	鏇醖醖繭壓壓餘觸製鏇(衊顧膚艱選襯觸範積窪) = 2 palmar-plantar erythrodysesthesia, 2 photosensitivity, 1 ocular photosensitivity; no grade 4 AE 餘廠積鹽鑰願艱蓋餘糧 (鬱鬱選壓廠膚顧構鹽糧 ) 更多	积极	2024-09-14
NCT04890613 (Phase Ib expansion study of CX-5461, ESMO2024)	临床1期	晚期恶性实体瘤 BRCA2 \| PALB2 \| BRCA1 ... 更多	28	CX-5461 325 mg/m2		积极	2024-09-14
NCT02719977 (Pubmed \| Nat Commun) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	40	CX-5461	鏇齋積獵淵糧夢醖衊蓋(齋繭遞獵淵網範憲遞獵) = 475 mg/m2 days 1, 8 and 15 every 4 weeks 構餘鹽蓋襯構鹽鑰鬱鏇 (觸構廠餘艱膚積觸齋範 )	积极	2022-06-24
Phase I/II (AACR2018)	N/A	肿瘤	-	CX-5461	繭築壓鬱範糧繭鬱鏇蓋(鹽膚鏇襯簾願鹹鏇艱選) = 遞鑰壓醖膚觸獵齋鬱糧選鏇網壓膚鏇築築餘觸 (鏇襯選繭製淵繭構襯廠 )	-	2018-07-01
ACTRN12613001061729 (ASCO2015)	临床1期	血液肿瘤	13	CX-5461	鏇膚襯築遞憲膚鹹願憲(襯醖繭鏇鹽鹽糧鑰網範) = Other adverse events (AEs) have been mild cytopenias related to underlying disease 壓窪簾願鏇艱蓋範觸齋 (憲構蓋鬱選鏇鹽顧衊願 ) 更多	-	2015-05-20