Phase 1/2, Multi-center, Open Label, Dose Escalation, Safety, Efficacy and PK Study of PRLX 93936 Administered IV 3 Days a Week for 3 Weeks Followed by a 9 Day Rest Period in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

To determine the maximum tolerated dose of, and response to, PRLX 93936 as treatment for patients with relapsed or relapsed/refractory multiple myeloma.

开始日期2012-03-01

申办/合作机构

Prolexys Pharmaceuticals, Inc.

NCT00528047

/ Completed临床1期

A Phase I, Multi-center, Open-Label, Dose-Escalation, Safety, Pharmacodynamic and Pharmacokinetic Study of PRLX 93936 Administered Intravenously Daily for Five Days Followed by a 23-Day Rest Period in Patients With Advanced Solid Tumors

The purpose of this study is to test the safety of PRLX 93936 and see what kind of effect it has on patients and their cancer. This study will also determine the highest dose of PRLX 93936 that can be given without causing adverse side effects and the dose of PRLX 93936 that should be used in future studies.

开始日期2007-08-01

申办/合作机构

Prolexys Pharmaceuticals, Inc.

100 项与 PRLX-93936 相关的临床结果

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100 项与 PRLX-93936 相关的转化医学

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100 项与 PRLX-93936 相关的专利（医药）

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项与 PRLX-93936 相关的文献（医药）

2025-09-02·Cancer Discovery

Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex.

Article

作者: Cameron, Michael D ; Martinez, Michael J ; Tran, Jessica ; Quispe Calla, Nirk E ; Guzman Huancas, Cesar ; Tang, Michelle T ; Lu, Joey ; Kuo, Calvin J ; Qiu, Tian ; Zhang, Tinghu ; Gray, Nathanael S ; Fernandez, Daniel ; Eckart, Michael ; Doench, John G ; Bian, Jing ; Corsello, Steven M ; Roth, Jennifer A ; Hinshaw, Stephen M ; Ji, Wenzhi ; Rees, Matthew G ; Jones, Hannah M ; Dwyer, Brendan G ; Phillips, Nick A ; Zhou, Christine Wenjie ; Charville, Gregory W ; Dixon, Scott J ; Colombo, Gianna M ; Yuan, Linjie

Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear pore complex. Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry-based proteomics, we discovered that the clinical drug PRLX-93936 is a molecular glue that binds and reprograms the TRIM21 ubiquitin ligase to degrade the nuclear pore complex. Upon compound-induced TRIM21 recruitment, the nuclear pore is ubiquitylated and degraded, resulting in the loss of short-lived cytoplasmic mRNA transcripts and induction of cancer cell apoptosis. Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and x-ray crystallography, while compound-induced TRIM21-nucleoporin complex formation was demonstrated through multiple orthogonal approaches in cells and in vitro. Phenotype-guided optimization yielded compounds with 10-fold greater potency and drug-like properties with robust pharmacokinetics and efficacy against pancreatic cancer xenografts and patient-derived organoids.

2025-04-18·ACS Chemical Biology

TRIM21-NUP98 Interface Accommodates Structurally Diverse Molecular Glue Degraders

Article

作者: Xue, Lei ; Li, Xiaomei ; Han, Ting ; Lu, Panrui ; Li, Jin ; Wang, Qingyang ; Cheng, Yalong ; Dou, Dengfeng ; Cao, Longzhi

Molecular glue degraders enable targeted protein degradation by bridging interactions between target proteins and E3 ubiquitin ligases. Whereas some target-E3 interfaces exhibit the capacity to accommodate structurally diverse degraders, the extent of this adaptability across molecular glue targets remains unclear. We recently identified (S)-ACE-OH as a molecular glue degrader that recruits the E3 ubiquitin ligase TRIM21 to the nuclear pore complex by recognizing NUP98, thereby inducing the degradation of nuclear pore proteins. Here, we analyzed public compound toxicity data across a large collection of cell lines and identified two additional molecular glue degraders, PRLX 93936 and BMS-214662, which engage the TRIM21-NUP98 interface to induce selective degradation of nuclear pore proteins. Additionally, we confirmed that HGC652, another TRIM21-dependent molecular glue degrader, also binds at this interface. Together with our previously characterized degrader (S)-ACE-OH, these findings demonstrate that the TRIM21-NUP98 interface can accommodate structurally diverse molecular glue degraders.

2022-03-01·CHEMICAL PAPERS

Iron chelates in the anticancer therapy

作者: Gachowska, Martyna ; Kielbik, Aleksander ; Puchala, Julia ; Wala, Kamila ; Chorazykiewicz, Katarzyna ; Rakoczy, Katarzyna ; Szlasa, Wojciech ; Kulbacka, Julita ; Kiszka, Karolina ; Saczko, Jolanta

Abstract:

Iron plays a significant role in the metabolism of cancer cells. In comparison with normal cells, neoplastic ones exhibit enhanced vulnerability to iron. Ferric ions target tumor via the ferroptotic death pathway—a process involving the iron-mediated lipid oxidation. Ferric ion occurs in complex forms in the physiological conditions. Apart from iron, ligands are the other factors to affect the biological activity of the iron complexes. In recent decades the role of iron chelates in targeting the growth of the tumor was extensively examined. The ligand may possess a standalone activity to restrict cancer’s growth. However, a wrong choice of the ligand might lead to the enhanced cancer cell’s growth in in vitro studies. The paper aims to review the role of iron complex compounds in the anticancer therapy both in the experimental and clinical applications. The anticancer properties of the iron complex rely both on the stability constant of the complex and the ligand composition. When the stability constant is high, the properties of the drug are unique. However, when the stability constant remains low, both components—ferric ions and ligands, act separately on the cells. In the paper we show how the difference in complex stability implies the action of ligand and ferric ions in the cancer cell. Iron complexation strategy is an interesting attempt to transport the anticancer Fe2+/3+ ions throughout the cell membrane and release it when the pH of the microenvironment changes. Last part of the paper summarizes the results of clinical trials and in vitro studies of novel iron chelates such as: PRLX 93,936, Ferumoxytol, Talactoferrin, DPC, Triapine, VLX600, Tachypyridine, Ciclopiroxamine, Thiosemicarbazone, Deferoxamine and Deferasirox.

项与 PRLX-93936 相关的新闻（医药）

2025-09-21

·BioArt

Cancer Discovery丨靶向核孔复合体的“分子胶水”为胰腺癌治疗带来新希望

撰文 | Qi 癌症治疗一直是医学界最具挑战性的领域之一，尤其是对于胰腺癌这种高度恶性、易转移且治疗手段有限的肿瘤类型。传统的化疗和靶向治疗虽然取得了一定进展，但患者的五年生存率仍然极低。近年来，科学家们开始将目光投向“非致癌基因成瘾”这一概念，即癌细胞依赖某些正常细胞中并不关键的蛋白或通路来维持其生存和增殖【1-3】，核孔复合体（Nuclear Pore Complex, NPC）就是这样一个引人注目的潜在靶点。NPC是细胞核与细胞质之间物质交换的关键通道，负责mRNA、蛋白质和代谢物的双向运输。由于癌细胞具有更高的转录活性和代谢需求，它们对NPC的依赖性远高于正常细胞。因此，若能选择性破坏NPC的功能，就有可能诱导癌细胞死亡，而不会对正常细胞造成严重伤害。然而，直接靶向NPC并非易事。它是由约30种不同核孔蛋白（Nucleoporins, NUPs）组成的巨大复合体，结构复杂，缺乏传统意义上的“可药性”口袋。近年来兴起的“分子胶水”技术为解决这一难题提供了新思路。分子胶水是一类能诱导蛋白质之间发生相互作用的小分子，虽已彻底改变了血液系统恶性肿瘤的治疗【4, 5】，但尚未获批用于常见的实体瘤。近日，来自斯坦福大学医学院的Steven M. Corsello团队等在Cancer Discovery杂志上合作发表了一篇一篇题为Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex的文章，他们通过大规模表型筛选、功能基因组学、蛋白质组学和结构生物学等多学科手段，揭示了临床阶段化合物PRLX-93936是一种新型分子胶水降解剂。它通过直接结合并重构TRIM21 E3泛素连接酶，使其靶向NPC，引发NPC蛋白的泛素化与降解，进而导致癌细胞中短寿命mRNA转录本丢失和凋亡发生。他们进一步通过药物化学优化，获得了活性提高10倍的衍生物JWZ-8-103，并在胰腺癌异种移植模型和患者来源类器官（PDO）中验证了其显著抗肿瘤效果。这些发现不仅为胰腺癌治疗提供了新的候选药物，也凸显了重新评估机制未知的临床阶段化合物在发现新型分子胶水方面的巨大潜力。该团队首先利用PRISM技术（一种高通量条形码细胞库筛选平台）对约900种癌细胞系进行PRLX处理后的存活率进行分析，发现胰腺癌、头颈部癌细胞系的抑制作用具有细胞系特异性，且PRLX的活性特征与TRIM21的mRNA表达量高度相关，TRIM21转录本含量越高，对PRLX的敏感性就越高。通过CRISPR/Cas9敲除或过表达TRIM21，将TRIM21确定为PRLX诱导细胞毒性的必需因子。随后，他们对PRLX进行了系统的结构-活性关系（structure-activity relationship, SAR）研究，合成了多个衍生物，并在表达TRIM21的PANC-1（人类胰腺癌细胞系）细胞中测试其活性，最终获得的JWZ-8-103在细胞水平IC50达到9.5 nM，比PRLX活性提高10倍，且完全依赖TRIM21表达。通过细胞热迁移实验（CETSA）、CRISPR碱基编辑扫描突变和表面等离子共振（SPR）等技术，该团队确认PRLX及其活性衍生物能直接结合TRIM21的PRYSPRY结构域，X射线晶体结构进一步揭示了JWZ-8-103与TRIM21结合的具体位点，包括关键氢键和疏水相互作用。随后，通过全局蛋白质组学、泛素化修饰组学和邻近标记蛋白质组学（TurbolD）等多重技术，他们发现PRLX处理能迅速且特异性地引起NPC蛋白的泛素化和降解，尤其是NUP214、NUP88、NUP35等NUPs。通过CRISPR筛选，他们发现靶向NUP98自水解结构域（APD）的sgRNA能显著挽救PRLX诱导的细胞死亡。PRLX处理导致MCL1、c-MYC等短寿命促生存蛋白的迅速减少。通过核质分离和单分子FISH（smFISH）技术，研究人员确认这些蛋白的mRNA在核内滞留，无法输出至胞质翻译，从而引发凋亡。患者来源类器官（PDO）能够更准确地重现肿瘤的三维结构和细胞间相互作用，且PDO具有更高的基因组稳定性，能准确维持表观遗传特征，并保持原肿瘤的异质性。为了评估PRLX及其类似物在PDO中与生物标志物相关的疗效，他们在65个PDO中验证了TRIM21表达与药物敏感性的相关性。结果显示高表达TRIM21的类器官对PRLX和JWZ-8-103高度敏感。在小鼠异种移植模型中，JWZ-8-103表现出优异的药代动力学特征和显著抗肿瘤活性，且耐受性良好。综上，这项工作揭示了PRLX-93936是一种通过重构TRIM21 E3连接酶靶向降解核孔复合体的分子胶水降解剂，不仅阐明了其作用机制，还成功开发出体内外均表现出显著抗肿瘤活性且药代特性更优的衍生物JWZ-8-103。未来，基于TRIM21的分子胶水降解剂有望成为靶向“不可成药”蛋白的新策略，尤其适用于高度依赖核质运输的癌症类型。原文链接： https://doi-org.libproxy1.nus.edu.sg/10.1158/2159-8290.CD-25-0271 制版人：十一参考文献 1. Nagel R, Semenova EA, Berns A. Drugging the addict: non-oncogene addiction as a target for cancer therapy. EMBO Rep. 2016;17:1516–31. 2. Hjaltelin JX, Izarzugaza JMG, Jensen LJ, Russo F, Westergaard D, Brunak S. Identification of hyper-rewired genomic stress non-oncogene addiction genes across 15 cancer types. NPJ Syst Biol Appl. 2019;5:27. 3. Di Marco T, Mazzoni M, Greco A, Cassinelli G. Non-oncogene dependencies: Novel opportunities for cancer therapy. BiochemPharmacol. 2024;228:116254. 4. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456– 65. 5. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau J-L, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–32. 6. Robbins P, Pierce M, Venkat RG, Peltier J, Rebentisch M, Lai S, et al. PRLX 93936, a novel, small molecule with broad antitumor activity in vitro. Mol Cancer Ther. 2007;6:A7– A7. 7. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. 制版人：十一学术合作组织（*排名不分先后）战略合作伙伴（*排名不分先后） · 转载须知【原创文章】BioArt原创文章，欢迎个人转发分享，未经允许禁止转载，所刊登的所有作品的著作权均为BioArt所拥有。BioArt保留所有法定权利，违者必究。 BioArt Med Plants 人才招聘近期直播推荐点击主页推荐活动关注更多最新活动！

信使RNA

2022-03-21

·生物谷

英国药理学: 盐酸益母草碱通过激活Nrf2信号通路减轻顺铂所致急性肾损伤中的铁死亡

越来越多的证据表明，铁死亡在顺铂所致急性肾损伤(AKI)的病理生理机制中起着关键作用。Nrf2信号通路调节氧化应激和脂质过氧化，并正向调节顺铂诱导的AKI(CI-AKI)。然而，其对CI-AKI后铁死亡的作用以及一种生物碱化合物盐酸益母草碱(LH)的作用尚不清楚。图片来源: https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/35303762/ 近日，吉林大学第一医院的研究者们在Br J Pharmacol杂志上发表了题为“Leonurine hydrochloride alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signaling pathway”的文章，该研究表明，Nrf2激活对CI-AKI的肾保护作用至少部分是通过抑制脂质过氧化物介导的铁死亡来实现的，并突出了LH作为CI-AKI治疗的潜力。在本研究中，研究者用小鼠顺铂诱导的AKI模型评价Nrf2和LH的抗铁死亡作用。体外观察LH对Erastin(铁死亡诱导剂)和RSL3(铁死亡激动剂)诱导的HK-2人PTEC铁死亡的影响。正如预期的那样，Nrf2缺失诱导了铁死亡相关蛋白的表达和体内铁的积累，进一步加重了CI-AKI。在体外，LH能激活Nrf2，防止铁蓄积、脂质过氧化和铁死亡，而siNrf2处理的细胞中这些作用被取消。此外，LH有效地改善了顺铂引起的肾损害。重要的是，LH激活了Nrf2抗氧化信号通路，抑制了与铁下垂相关的形态和生化指标的变化，如丙二醛水平、超氧化物歧化酶和谷胱甘肽的耗竭以及Gpx4和XCT的下调。此外，Nrf2敲除小鼠在CI-AKI后发生铁死亡的敏感性高于对照组，而LH对Nrf2敲除小鼠AKI和铁死亡的保护作用在Nrf2敲除小鼠中被基本消除。 LH减轻顺铂诱导的体内铁死亡的作用依赖于Nrf2基因的表达图片来源: https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/35303762/ 总之，该研究揭示了上调Nrf2对预防铁死亡从而缓解CI-AKI的重要意义。这一结论源于三个关键发现。首先，Nrf2 敲除小鼠更容易受到顺铂引起的肾损伤和铁死亡的影响。第二，LH通过激活抗氧化信号分子Nrf2，抑制铁死亡相关的形态和生化改变，对顺铂诱导的AKI具有保护作用。最后，用LH处理Nrf2敲除小鼠和Nrf2 siRNA HK-2细胞，在体内和体外几乎不能挽救顺铂和RSL3诱导的铁死亡和肾脏损伤。本研究进一步理解了Nrf2抑制铁离子腐蚀的机制，并为研究Nrf2激活剂在顺铂诱导的AKI中的抗铁离子腐蚀活性提供了策略。仍需临床试验进一步的研究LH治疗顺铂所致急性肾损伤的安全性和有效性。参考文献 Jianqiang Hu et al. Leonurine hydrochloride alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signaling pathway. Br J Pharmacol. 2022 Mar 18. doi: 10.1111/bph.15834. 内容来源于网络，如有侵权，请联系删除，谢谢

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06098

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
多发性骨髓瘤	临床2期	美国	Prolexys Pharmaceuticals, Inc.	2012-03-01
晚期恶性实体瘤	临床1期	美国	Prolexys Pharmaceuticals, Inc.	2007-08-01