更新于：2024-11-01

DHX9

更新于：2024-11-01

基本信息

别名

ATP-dependent RNA helicase A、DDX9、DEAH box protein 9

+ [9]

简介

Multifunctional ATP-dependent nucleic acid helicase that unwinds DNA and RNA in a 3' to 5' direction and that plays important roles in many processes, such as DNA replication, transcriptional activation, post-transcriptional RNA regulation, mRNA translation and RNA-mediated gene silencing (PubMed:9111062, PubMed:11416126, PubMed:12711669, PubMed:15355351, PubMed:16680162, PubMed:17531811, PubMed:20669935, PubMed:21561811, PubMed:24049074, PubMed:25062910, PubMed:24990949, PubMed:28221134). Requires a 3'-single-stranded tail as entry site for acid nuclei unwinding activities as well as the binding and hydrolyzing of any of the four ribo- or deoxyribo-nucleotide triphosphates (NTPs) (PubMed:1537828). Unwinds numerous nucleic acid substrates such as double-stranded (ds) DNA and RNA, DNA:RNA hybrids, DNA and RNA forks composed of either partially complementary DNA duplexes or DNA:RNA hybrids, respectively, and also DNA and RNA displacement loops (D- and R-loops), triplex-helical DNA (H-DNA) structure and DNA and RNA-based G-quadruplexes (PubMed:20669935, PubMed:21561811, PubMed:24049074). Binds dsDNA, single-stranded DNA (ssDNA), dsRNA, ssRNA and poly(A)-containing RNA (PubMed:9111062, PubMed:10198287). Binds also to circular dsDNA or dsRNA of either linear and/or circular forms and stimulates the relaxation of supercoiled DNAs catalyzed by topoisomerase TOP2A (PubMed:12711669). Plays a role in DNA replication at origins of replication and cell cycle progression (PubMed:24990949). Plays a role as a transcriptional coactivator acting as a bridging factor between polymerase II holoenzyme and transcription factors or cofactors, such as BRCA1, CREBBP, RELA and SMN1 (PubMed:11149922, PubMed:9323138, PubMed:9662397, PubMed:11038348, PubMed:11416126, PubMed:15355351, PubMed:28221134). Binds to the CDKN2A promoter (PubMed:11038348). Plays several roles in post-transcriptional regulation of gene expression (PubMed:28221134, PubMed:28355180). In cooperation with NUP98, promotes pre-mRNA alternative splicing activities of a subset of genes (PubMed:11402034, PubMed:16680162, PubMed:28221134, PubMed:28355180). As component of a large PER complex, is involved in the negative regulation of 3' transcriptional termination of circadian target genes such as PER1 and NR1D1 and the control of the circadian rhythms (By similarity). Acts also as a nuclear resolvase that is able to bind and neutralize harmful massive secondary double-stranded RNA structures formed by inverted-repeat Alu retrotransposon elements that are inserted and transcribed as parts of genes during the process of gene transposition (PubMed:28355180). Involved in the positive regulation of nuclear export of constitutive transport element (CTE)-containing unspliced mRNA (PubMed:9162007, PubMed:10924507, PubMed:11402034). Component of the coding region determinant (CRD)-mediated complex that promotes cytoplasmic MYC mRNA stability (PubMed:19029303). Plays a role in mRNA translation (PubMed:28355180). Positively regulates translation of selected mRNAs through its binding to post-transcriptional control element (PCE) in the 5'-untranslated region (UTR) (PubMed:16680162). Involved with LARP6 in the translation stimulation of type I collagen mRNAs for CO1A1 and CO1A2 through binding of a specific stem-loop structure in their 5'-UTRs (PubMed:22190748). Stimulates LIN28A-dependent mRNA translation probably by facilitating ribonucleoprotein remodeling during the process of translation (PubMed:21247876). Plays also a role as a small interfering (siRNA)-loading factor involved in the RNA-induced silencing complex (RISC) loading complex (RLC) assembly, and hence functions in the RISC-mediated gene silencing process (PubMed:17531811). Binds preferentially to short double-stranded RNA, such as those produced during rotavirus intestinal infection (PubMed:28636595). This interaction may mediate NLRP9 inflammasome activation and trigger inflammatory response, including IL18 release and pyroptosis (PubMed:28636595). Finally, mediates the attachment of heterogeneous nuclear ribonucleoproteins (hnRNPs) to actin filaments in the nucleus (PubMed:11687588). (Microbial infection) Plays a role in HIV-1 replication and virion infectivity (PubMed:11096080, PubMed:19229320, PubMed:25149208, PubMed:27107641). Enhances HIV-1 transcription by facilitating the binding of RNA polymerase II holoenzyme to the proviral DNA (PubMed:11096080, PubMed:25149208). Binds (via DRBM domain 2) to the HIV-1 TAR RNA and stimulates HIV-1 transcription of transactivation response element (TAR)-containing mRNAs (PubMed:9892698, PubMed:11096080). Involved also in HIV-1 mRNA splicing and transport (PubMed:25149208). Positively regulates HIV-1 gag mRNA translation, through its binding to post-transcriptional control element (PCE) in the 5'-untranslated region (UTR) (PubMed:16680162). Binds (via DRBM domains) to a HIV-1 double-stranded RNA region of the primer binding site (PBS)-segment of the 5'-UTR, and hence stimulates DHX9 incorporation into virions and virion infectivity (PubMed:27107641). Also plays a role as a cytosolic viral MyD88-dependent DNA and RNA sensors in plasmacytoid dendritic cells (pDCs), and hence induce antiviral innate immune responses (PubMed:20696886, PubMed:21957149). Binds (via the OB-fold region) to viral single-stranded DNA unmethylated C-phosphate-G (CpG) oligonucleotide (PubMed:20696886).

关联

项与 DHX9 相关的药物

ATX-559

靶点

DHX9

作用机制

DHX9抑制剂

在研机构

Accent Therapeutics, Inc.初创企业

原研机构

Accent Therapeutics, Inc.初创企业

在研适应症

复发性乳腺癌 [+4]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

ATX-968

靶点

BRIP1 x DHX9

作用机制

BRIP1 modulators [+1]

在研机构

Accent Therapeutics, Inc.初创企业

原研机构

Accent Therapeutics, Inc.初创企业

在研适应症

结直肠癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

Compound 1(Accent Therapeutics)

靶点

DHX9

作用机制

DHX9抑制剂

在研机构

Accent Therapeutics, Inc.初创企业

原研机构

Accent Therapeutics, Inc.初创企业

在研适应症

子宫内膜癌 [+2]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 DHX9 相关的临床试验

NCT06625515 / Recruiting临床1期

A Phase 1/2, Open-Label, Dose-Escalation and Expansion First-In-Human Study of ATX-559, an Oral Inhibitor of the Helicase DHX9, in Patients with Locally Advanced or Metastatic Solid Tumors and Molecularly Defined Cancers

The goal of this study is to identify a safe and tolerated dose of the orally administered DHX9 inhibitor ATX-559. In addition, this study will evaluate the pharmacokinetics, pharmacodynamics and preliminary antitumor activity of ATX-559 in patients with advanced solid tumors and molecularly defined cancers.

开始日期2024-10-01

申办/合作机构

Accent Therapeutics, Inc.初创企业

100 项与 DHX9 相关的临床结果

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100 项与 DHX9 相关的转化医学

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0 项与 DHX9 相关的专利（医药）

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943

项与 DHX9 相关的文献（医药）

2024-11-01·Journal of Biological Chemistry

The RNA-binding protein PCBP1 modulates transcription by recruiting the G-quadruplex-specific helicase DHX9

Article

作者: Howe, Philip H. ; Dalton, Annamarie C. ; Howe, Philip H ; Fréreux, Cécile ; Howley, Breege V ; Palanisamy, Viswanathan ; Dincman, Toros A ; Mohanty, Bidyut K ; Dincman, Toros A. ; Dalton, Annamarie C ; Mohanty, Bidyut K. ; Howley, Breege V. ; Karam, Joseph A Q ; Karam, Joseph A.Q.

PCBP1, polycytosine (poly(C)) binding protein 1, an RNA and single-stranded DNA (ssDNA) binding protein, binds poly(C) DNA tracts but it remains unclear whether its ability to bind ssDNA contributes to transcriptional regulation. Here, we report that PCBP1's DNA binding sites are enriched at transcription start sites and that by binding to promoter regions, PCBP1 regulates transcription in addition to splicing and translation. At PCBP1 target genes, we show that PCBP1 interacts with several RNA/DNA hybrid (R-loop) associated G-quadruplex resolving helicases. Furthermore, we find that PCBP1 interacts with RNA Helicase A (DHX9) to modulate transcription by regulating DHX9 accumulation and activity. PCBP1 depletion leads to defects in R-loop processing and dysregulation of transcription of PCBP1 target genes. PCBP1's high sequence specificity and interaction with helicases suggest that its mechanism in transcription involves guiding helicases to specific loci during transcription, thereby modulating their activity.

2024-10-11·ACS Infectious Diseases

2-Aryl-Benzoimidazoles as Type II NADH Dehydrogenase Inhibitors of Mycobacterium tuberculosis

Article

作者: Kalia, Nitin Pal ; Saha, Pallavi ; Sharma, Deepak K. ; Sau, Shashikanta

The nonproton pumping type II NADH dehydrogenase in Mycobacterium tuberculosis is essential for meeting the energy needs in terms of ATP under normal aerobic and stressful hypoxic environmental states. Type II NADH dehydrogenase conduits electrons into the electron transport chain in Mycobacterium tuberculosis, which results in ATP synthesis. Therefore, the inhibition of NDH-2 ensures the abolishment of the entire ATP synthesis machinery. Also, type II NADH dehydrogenase is absent in the mammalian genome, thus making it a potential target for antituberculosis drug discovery. Herein, we have screened a commercially available library of drug-like molecules and have identified a hit having a benzimidazole core moiety (6, H37Rv mc²6230; minimum inhibitory concentration (MIC) = 16 μg/mL and ATP IC₅₀ = 0.23 μg/mL) interfering with the oxidative phosphorylation pathway. Extensive medicinal chemistry optimization resulted in analogue 8, with MIC = 4 μg/mL and ATP IC₅₀ = 0.05 μg/mL against the H37Rv mc²6230 strain of Mycobacterium tuberculosis. Compounds 6 and 8 were found to be active against mono- and multidrug-resistant mycobacterium strains and demonstrated a bactericidal response. The Peredox-mCherry experiment and identification of single-nucleotide polymorphisms in mutants of CBR-5992 (a known type II NADH dehydrogenase inhibitor) were used to confirm the molecules as inhibitors of the type II NADH dehydrogenase enzyme. The safety index >10 for the test active molecules revealed the safety of test molecules.

2024-10-01·Preparative Biochemistry & Biotechnology

Use of ultrasound to increase the catalytic activity of α-L-rhamnosidase

Article

作者: Qi, Chen ; Lin, Yanling ; Yu, Kunpeng ; Li, Le ; Li, Lijun

α-L-rhamnosidase (Rha) is ubiquitous in nature and has high feasibility in the food and biotechnology industries. A green and environmentally friendly method was used to improve the activity of Rha. Here, we show that the effects of ultrasound treatment on the Rha. Ultrasonic treatment at 80 W for 10 min yielded the highest enzyme activity. Treatment increased enzyme activity by 26.3% and half-life by 124 min. Further, treatment increased the catalytic efficiency of Rha and increased the substrate conversion rate by 33.88%. These results demonstrate that ultrasound increases the catalytic activity and stability of Rha. Thus, ultrasonic treatment of Rha is cost-effective on the industrial scale.

项与 DHX9 相关的新闻（医药）

2024-10-28

·药明康德

“癌症之王”患者6个月生存率超90%的KRAS靶向小分子；疾病控制率达100%的FGFR3靶向疗法…… | 一周盘点

▎药明康德内容团队编辑本期看点 1. 口服选择性FGFR3靶向疗法TYRA-300的早期临床结果亮眼，接受剂量≥90 mg/天的FGFR3突变转移性尿路上皮癌（mUC）患者的疾病控制率（DCR）为100%。 2. 泛RAS抑制剂RMC-6236在经治胰腺导管腺癌（PDAC）患者中展现出令人鼓舞的抗肿瘤活性和安全性，携带任意RAS突变的PDAC患者在6个月的总生存率为91%。 3. 治疗转移性透明细胞肾细胞癌（ccRCC）的小分子HIF-2a抑制剂casdatifan在一项1/1b期临床试验中的DCR达81%。药明康德内容团队整理 TYRA-300：公布1/2期临床试验数据 Tyra Biosciences公司公布了其潜在“first-in-class”的口服疗法TYRA-300治疗转移性尿路上皮癌（mUC）患者的1/2期研究SURF301的数据。TYRA-300是一种FGFR3选择性抑制剂，旨在避免抑制FGFR1、FGFR2和FGFR4时产生的毒性，且无论是否存在与耐药性相关的FGFR3门卫（gatekeeper）突变都能发挥作用。截至2024年8月15日的数据，接受剂量≥90 mg/天的FGFR3突变mUC患者的DCR为100%，54.5%（6/11）的患者达到部分缓解（PR），其中3例仍在治疗中，接受90 mg/天剂量的患者中有50%（5/10）达到PR。安全性方面，TYRA-300的耐受性总体良好，FGFR2和FGFR1相关毒性不常见。 RMC-6236：公布1/1b期临床试验数据 Revolution Medicines公司宣布，其在研泛RAS抑制剂RMC-6236在经治胰腺导管腺癌患者中展现出令人鼓舞的抗肿瘤活性和安全性。RMC-6236是一款口服、可靶向突变和野生型RAS在GTP结合（具活性，ON）状态下的选择性抑制剂。此次公布的1/1b期多中心、开放标签、剂量递增和剂量扩展研究RMC-6236-001旨在评估RMC-6236作为单药治疗携带RAS突变或野生型RAS晚期实体瘤患者的效果。结果显示，RMC-6236单药作为二线疗法可改善携带任意RAS突变PDAC患者的中位无进展生存期（PFS）与总生存期（OS）。在二线治疗中，携带KRAS G12X突变（KRAS G12X指的是KRAS蛋白第12位的甘氨酸因为基因突变，转换成其它氨基酸）的PDAC患者的中位PFS为8.5个月，中位OS为14.5个月。携带任意RAS突变的PDAC患者在二线治疗中的中位PFS为7.6个月，中位OS为14.5个月。携带KRAS G12X突变与携带任意RAS突变的PDAC患者在6个月时的总生存率分别为89%与91%。在二线治疗组中，携带KRAS G12X突变患者的客观缓解率（ORR）为29%，在三线及以上治疗组（3L+）中为22%，这些患者的DCR分别为91%和89%。目前该疗法的3期临床试验RASolute 302正在进行中。 Casdatifan：公布1/1b期临床试验数据 Arcus Biosciences公司公布了其在研小分子HIF-2a抑制剂casdatifan治疗转移性透明细胞肾细胞癌的1/1b期临床试验数据。HIF-2a是一种致癌转录因子，参与多个器官和肿瘤中的氧感应。由于VHL通路的基因异常，ccRCC几乎普遍与HIF-2a失调有关。通过选择性抑制HIF-2a，casdatifan可使一系列涉及肿瘤增殖和存活、耐药性和血管生成的通路失效，从而导致癌细胞死亡。截至2024年8月30日的数据，中位随访时间为11个月。在100 mg每日剂量扩展队列（n=32）中，DCR达81%，ORR为34%（2个待确认的缓解），许多患者仍在接受治疗。安全性方面，casdatifan具有可接受且可管理的安全性。 ▲Casdatifan治疗ccRCC患者的1/1b期试验数据（图片来源：参考资料[7]） NX-5948：公布1a/1b期临床试验数据 Nurix Therapeutics公司公布其在研蛋白降解剂NX-5948在治疗复发/难治性华氏巨球蛋白血症（WM）患者的1a/1b期临床试验中的最新数据。NX-5948是一种口服、可穿越血脑屏障的小分子布鲁顿氏酪氨酸激酶（BTK）蛋白降解剂。Nurix此前报告称，NX-5948对一系列对现有BTK抑制剂耐药的肿瘤细胞系表现出高效的抑制活性，这对于经过大量前期治疗的B细胞恶性肿瘤患者群体尤为重要。截至2024年10月10日的数据，在9例可评估应答的患者中，7例患者（77.8%）出现客观缓解，两例患者病情稳定（22.2%）。所有7例缓解均在8周的首次评估中观察到，其中5例患者仍在接受治疗，2例患者的治疗时间超过一年。不论患者基线MYD88和CXCR4的突变状态如何，均观察到应答。 Bel-sar（AU-011）：公布1期临床试验数据 Aura Biosciences公司宣布，其在研病毒样偶联药物（VDC）bel-sar（AU-011）在治疗非肌层浸润性膀胱癌（NMIBC）患者的1期临床试验中获得积极早期数据。Bel-sar由靶向肿瘤表面表达的糖蛋白的类病毒颗粒（VLP）与可由光激活的细胞毒性药物偶联生成。它被设计为具有双重作用机制，既能诱导肿瘤细胞坏死，又能激发强大且持久的抗肿瘤免疫反应。该试验共纳入了13名患者，主要终点是评估bel-sar单独使用（n=5）和bel-sar结合光激活（n=8）局部给药的安全性和可行性。次要终点是评估生物活性及肿瘤微环境（TME）中的免疫介导变化。13名研究参与者中，10名为低级别疾病患者，另外3名为高级别疾病患者。在接受bel-sar结合光激活治疗的患者（n=8）中，5名低级别疾病患者中有4名在组织病理学评估中显示无肿瘤细胞残留，达到了临床完全缓解（CR）。3名高级别疾病患者中有2名在膀胱镜检查中显示肿瘤明显缩小。 ONCT-534：公布1/2期临床试验数据 Oncternal Therapeutics公司公布了其在研雄激素受体（AR）抑制剂ONCT-534治疗复发性或难治性转移性去势抵抗性前列腺癌（mCRPC）患者的1/2期研究的最新数据。ONCT-534在前列腺癌模型中对未发生突变的AR以及多种形式的AR突变和异常都具有活性。ONCT-534具有治疗对AR通路抑制剂耐药（包括AR扩增、AR配体结合域突变或AR配体结合域缺失型剪接变体）的mCRPC患者的潜力。截至2024年9月30日的数据，每天两次的给药方案耐受性良好，没有出现与治疗相关的3级或更高级别的毒性反应。1名患者在接受每日两次160 mg剂量ONCT-534治疗后，前列腺特异性抗原（PSA）升高，但在随后4周以每日两次300 mg剂量ONCT-534治疗后，PSA下降了50%，同时计算机断层扫描（CT）显示与基线相比，靶病灶减少了16%。循环肿瘤细胞（CTCs）的计数和生物标志物分析显示，在另外6名患者中，ONCT-534对AR调控基因的表达和AR的核转位有令人鼓舞的效果。 Lunresertib+camonsertib：公布1期联合治疗试验数据 Repare Therapeutics公司公布了1期临床试验MYTHIC的最新数据，该试验评估了其PKMYT1抑制剂lunresertib和口服小分子ATR抑制剂camonsertib（lunre+camo）的组合疗法。在这项分析中，Repare公司对接受2期段推荐剂量（RP2D）的患者进行了约9个月的随访。结果显示，lunre+camo在保持临床疗效的同时，成功地减轻了与抗肿瘤药物机制相关的贫血。此外，在这些患者中未观察到任何级别的血小板减少或严重的中性粒细胞减少。 ATX-559：IND申请获得FDA许可 Accent Therapeutics公司宣布美国FDA已批准其潜在“first-in-class”的DHX9抑制剂ATX-559的IND申请，可在实体瘤患者中开展1期研究，重点关注BRCA1/2缺陷的乳腺癌和微卫星不稳定性高（MSI-H）和/或错配修复缺陷（dMMR）的实体瘤，预计首例患者将在2024年第四季度接受给药。 DHX9是一种DNA/RNA螺旋酶，据报道在复制、转录、翻译、RNA剪接、RNA处理以及维持基因稳定性等方面发挥着重要作用，该酶是一个有吸引力的新肿瘤学靶点。ATX-559通过抑制DHX9可利用关键的肿瘤弱点，导致癌症特异性细胞死亡。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看） [1] Revolution Medicines Presents Updated Data from RMC-6236 Monotherapy Study in Patients with Advanced Pancreatic Ductal Adenocarcinoma. Retrieved October 23, 2024 from https://www.globenewswire.com/en/news-release/2024/10/23/2967583/0/en/Revolution-Medicines-Presents-Updated-Data-from-RMC-6236-Monotherapy-Study-in-Patients-with-Advanced-Pancreatic-Ductal-Adenocarcinoma.html [2] Multiple Clinical Complete Responses Demonstrated Following Single Low Dose Administration of Bel-sar in Patients with Non-Muscle-Invasive Bladder Cancer (NMIBC) in Ongoing Phase 1 Trial. Retrieved October 18, 2024, from https://ir.aurabiosciences.com/news-releases/news-release-details/multiple-clinical-complete-responses-demonstrated-following [3] Oncternal Therapeutics Announces Updated Safety and Efficacy Data for Phase 1/2 Study of ONCT-534 for the Treatment of R/R Metastatic Castration-Resistant Prostate Cancer. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/22/2967000/0/en/Oncternal-Therapeutics-Announces-Updated-Safety-and-Efficacy-Data-for-Phase-1-2-Study-of-ONCT-534-for-the-Treatment-of-R-R-Metastatic-Castration-Resistant-Prostate-Cancer.html [4] Nurix Therapeutics Presents Positive Results from the Ongoing Clinical Trial of Its BTK Degrader NX-5948 in Patients with Relapsed/Refractory Waldenstrom’s Macroglobulinemia. Retrieved October 21, 2024, from https://www.globenewswire.com/en/news-release/2024/10/19/2965795/0/en/Nurix-Therapeutics-Presents-Positive-Results-from-the-Ongoing-Clinical-Trial-of-Its-BTK-Degrader-NX-5948-in-Patients-with-Relapsed-Refractory-Waldenstrom-s-Macroglobulinemia.html [5] Repare Therapeutics Announces Updated Positive Safety and Tolerability Results from the Phase 1 MYTHIC Clinical Trial. Retrieved October 25, 2024, from https://ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-announces-updated-positive-safety-and [6] Tyra Biosciences Reports Interim Clinical Proof-of-Concept Data for TYRA-300, an Investigational Oral FGFR3-Selective Inhibitor, in Phase 1/2 SURF301 Study in Patients with Metastatic Urothelial Cancer (mUC). Retrieved October 25, 2024, from https://www.callunapharma.com/wp-content/uploads/2024/01/Calluna_Pharma_Launch_PR.pdf [7] First Clinical Data for Arcus Biosciences’ HIF-2a Inhibitor, Casdatifan, Showed Promising Clinical Activity and Tumor Shrinkage in Patients with Metastatic Kidney Cancer. Retrieved October 25, 2024, from https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/First-Clinical-Data-for-Arcus-Biosciences-HIF-2a-Inhibitor-Casdatifan-Showed-Promising-Clinical-Activity-and-Tumor-Shrinkage-in-Patients-with-Metastatic-Kidney-Cancer/default.aspx [8] Interius BioTherapeutics Doses First Patient with in vivo Chimeric Antigen Receptor (CAR) Gene Therapy for B-cell Malignancies. Retrieved October 25, 2024, from https://interiusbio.com/2024/10/interius-biotherapeutics-doses-first-patient-with-in-vivo-chimeric-antigen-receptor-car-gene-therapy-for-b-cell-malignancies/ [9] Spur Therapeutics Showcases Positive New Data from Phase 1/2 GALILEO-1 Trial of FLT201, Its Novel Gene Therapy Candidate for Gaucher Disease, in Oral Presentation at ESGCT 31st Annual Congress. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/23/2967469/0/en/Spur-Therapeutics-Showcases-Positive-New-Data-from-Phase-1-2-GALILEO-1-Trial-of-FLT201-Its-Novel-Gene-Therapy-Candidate-for-Gaucher-Disease-in-Oral-Presentation-at-ESGCT-31st-Annua.html [10] Find Therapeutics Announces First Subject Dosed in Phase 1 Clinical Study of FTX-101. Retrieved October 25, 2024, from https://www.prnewswire.com/news-releases/find-therapeutics-announces-first-subject-dosed-in-phase-1-clinical-study-of-ftx-101-302278520.html [11] Zymeworks Announces First Patient Dosed in Phase 1 Clinical Trial Evaluating ZW171 in Advanced Mesothelin-Expressing Cancers. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/21/2966023/0/en/Zymeworks-Announces-First-Patient-Dosed-in-Phase-1-Clinical-Trial-Evaluating-ZW171-in-Advanced-Mesothelin-Expressing-Cancers.html [12] Aligos Therapeutics Announces U.S. FDA Clearance of IND Application for ALG-000184. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/22/2966892/0/en/Aligos-Therapeutics-Announces-U-S-FDA-Clearance-of-IND-Application-for-ALG-000184.html [13] Pierre Fabre宣布在PFL-002/VERT-002的I/II期首次给药，这是一种MET改变的NSCLC靶向治疗. Retrieved October 25, 2024, from https://www.prnasia.com/story/465694-1.shtml [14] Inozyme Pharma Announces Positive Interim Data from Phase 1 SEAPORT 1 Trial of INZ-701. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/24/2968997/0/en/Inozyme-Pharma-Announces-Positive-Interim-Data-from-Phase-1-SEAPORT-1-Trial-of-INZ-701.html [15] Apogee Therapeutics Announces Results Up to 9 Months from Phase 1 Trial of APG777, its Novel Half-Life Extended Anti-IL-13 Antibody for the Treatment for Atopic Dermatitis and Other Inflammatory Diseases. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/24/2968646/0/en/Apogee-Therapeutics-Announces-Results-Up-to-9-Months-from-Phase-1-Trial-of-APG777-its-Novel-Half-Life-Extended-Anti-IL-13-Antibody-for-the-Treatment-for-Atopic-Dermatitis-and-Other.html [16] BridgeBio Shares Positive Data from High Dose Cohort of Phase 1/2 CANaspire Study of Gene Therapy BBP-812 for Canavan Disease at ESGCT 2024. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/24/2968601/0/en/BridgeBio-Shares-Positive-Data-from-High-Dose-Cohort-of-Phase-1-2-CANaspire-Study-of-Gene-Therapy-BBP-812-for-Canavan-Disease-at-ESGCT-2024.html [17] Precision BioSciences Receives First Approval of Clinical Trial Application to Initiate PBGENE-HBV First-In-Human Study for the Treatment of Chronic Hepatitis B. Retrieved October 25, 2024, from https://investor.precisionbiosciences.com/news-releases/news-release-details/precision-biosciences-receives-first-approval-clinical-trial [18] First Patients Dosed in Phase 1 Clinical Study of ImmunityBio’s CAR-NK Cell Therapy for the Treatment of Relapsed B-Cell Non-Hodgkin Lymphoma. Retrieved October 25, 2024, from https://ir.immunitybio.com/news-releases/news-release-details/first-patients-dosed-phase-1-clinical-study-immunitybios-car-nk?field_nir_news_date_value[min]= [19] Aprea Therapeutics Presents Preliminary Findings on Oral WEE1 Inhibitor APR-1051 at EORTC-NCI-AACR International Conference on Molecular Targets and Therapeutics. Retrieved October 25, 2024, from https://ir.aprea.com/news-releases/news-release-details/aprea-therapeutics-presents-preliminary-findings-oral-wee1 [20] Autolus Therapeutics Presents Clinical Data Update at the 2024 Lymphoma, Leukemia & Myeloma Congress. Retrieved October 25, 2024, from　https://www.globenewswire.com/news-release/2024/10/16/2964125/0/en/Autolus-Therapeutics-Presents-Clinical-Data-Update-at-the-2024-Lymphoma-Leukemia-Myeloma-Congress.html [21] Accent Therapeutics Announces FDA Clearance of IND Application for ATX-559, a First-In-Class Oral DHX9 Inhibitor. Retrieved October 25, 2024, from　https://www.prnewswire.com/news-releases/accent-therapeutics-announces-fda-clearance-of-ind-application-for-atx-559-a-first-in-class-oral-dhx9-inhibitor-302285845.html [22] Calluna Pharma launches and announces EUR 75 million Series A financing to develop novel therapies for inflammatory and fibrotic diseases. Retrieved October 25, 2024, from　 https://www.businesswire.com/news/home/20241023939388/en/Calluna-Pharma-Successfully-Completes-Phase-1-Clinical-Study-of-CAL101-a-First-in-Class-Therapeutic-for-Fibrotic-and-Fibro-Inflammatory-Indications/#:~:text=Calluna%20Pharma%20Successfully%20Completes%20Phase%201%20Clinical%20Study,CAL101%20is%20now%20entering%20Phase%202%20clinical%20development 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床结果基因疗法临床终止

2024-10-24

·PRNewswire

Accent Therapeutics Announces FDA Clearance of IND Application for ATX-559, a First-In-Class Oral DHX9 Inhibitor

Enables ATX-559 Phase 1 study in solid tumor patients with a focus on BRCA1/2-deficient breast cancer and solid tumors with microsatellite instability (MSI-H) and/or deficient mismatch repair (dMMR); first patient dosed anticipated in Q4 2024 Second program targeting KIF18A on track to enter clinical trials in early 2025, underscoring rapid advancement of novel therapies Clinical Advisory Board (CAB) of global oncology drug development experts formed to support the advancement of Accent's clinical pipeline LEXINGTON, Mass., Oct. 24, 2024 /PRNewswire/ -- Accent Therapeutics, a biopharmaceutical company pioneering novel small molecule targeted cancer therapeutics, today announced that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for ATX-559, a first-in-class DHX9 inhibitor. In addition, Accent has established a Clinical Advisory Board (CAB) to help guide the Company's progress in the clinic. The ATX-559 Phase 1/2 trial (NCT06625515) is expected to begin dosing patients with a focus on BRCA1- or BRCA2-deficient breast cancer and patients with MSI-H and/or dMMR solid tumors (including certain patients with colorectal, endometrial, gastric, and other cancers) in the fourth quarter of 2024. The clinical study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ATX-559. For more information on the trial, visit the study page on ClinicalTrials.gov. "The FDA's IND clearance is a pivotal moment for Accent Therapeutics, propelling our lead program into the clinical arena. This milestone not only validates our scientifically rigorous approach to identifying innovative targets, but also brings us one step closer to helping cancer patients with significant unmet need," said Jason Sager, M.D., Chief Medical Officer of Accent Therapeutics. "ATX-559 has shown remarkable promise in preclinical studies, and we're excited to now evaluate its potential to meaningfully improve outcomes for patients facing these challenging malignancies." As Accent prepares to initiate its first clinical trial, the company has also established a Clinical Advisory Board to guide the advancement of its clinical pipeline. The Clinical Advisory Board consists of renowned clinician-scientists and leaders whose strategic insights and clinical expertise will support the Company's efforts to advance its mission of creating life-changing therapeutics for patients living with cancer. The newly formed Clinical Advisory Board includes: Lillian L. Siu, M.D., FRCPC, medical oncologist, Director of the Phase I Program at Princess Margaret Cancer Centre, Professor of Medicine at the University of Toronto, and President-Elect of the American Association for Cancer Research (AACR) Josep Tabernero, M.D., Ph.D., Professor of Medicine, Head of the Medical Oncology Department at the Vall d'Hebron Barcelona Hospital Campus, and Director of the Vall d'Hebron Institute of Oncology (VHIO) Sam Blackman, M.D., Ph.D., co-founder and Head of Research and Development of Day One Biopharmaceuticals "We are honored to have such distinguished experts join our Clinical Advisory Board as we advance our programs into the clinic," said Shakti Narayan, Ph.D., J.D., Chief Executive Officer of Accent Therapeutics. "Their experience will be invaluable as we work to bring transformative therapies to patients." Accent is also on track to advance its second program, targeting KIF18A in chromosomally instable tumors, into the clinic with a Phase 1 trial anticipated to begin in early 2025. This marks an exciting phase of growth for the company as it continues to build on its foundational platform technology to develop innovative cancer therapies. About ATX-559 ATX-559 is a first-in-class DHX9 inhibitor with the potential to address high unmet need indications not adequately served by existing therapies, such as BRCA-deficient tumors (including breast, ovarian, and others), MSI-H and/or dMMR cancers (including colorectal, endometrial, gastric, and others) and additional undisclosed cancer types representing large patient populations. DHX9 is a DNA/RNA helicase that has been reported to play important roles in replication, transcription, translation, RNA splicing, RNA processing, and maintenance of genomic stability. Inhibition of DHX9 exploits key tumor vulnerabilities, resulting in cancer-specific cell death, and thus this enzyme represents a compelling novel oncology target. Accent retains full worldwide rights to ATX-559 and the DHX9 program. About KIF18A Accent's second lead program is a potential best-in-class inhibitor for KIF18A which may address a large patient population across several cancer indications, including ovarian and triple negative breast cancer (TNBC). KIF18A is a mitotic kinesin motor protein critical for cell division in select tumors with chromosomal instability. A subset of tumor cells with an abnormal number of chromosomes (aneuploid) are reliant on KIF18A and show rapid cell killing in vitro and in vivo upon KIF18A inhibitor treatment, while cells with normal numbers of chromosomes (euploid) are unaffected. About Accent Therapeutics Accent Therapeutics is pioneering a new class of small molecule precision cancer therapies targeting critical intracellular dependencies that span multiple types of cancer. Building upon industry-leading expertise in RNA-modifying proteins (RMPs) and the systematic mapping of both the RMP space and adjacent high-value areas for drug discovery, the company is building a flexible model that allows for a diversity of approaches to developing potentially transformative biomarker-driven cancer medicines. Accent's therapies are designed for both novel and known, but suboptimally addressed, high-impact oncology targets with the potential to benefit large patient populations with significant unmet need. For more information on Accent's mission to translate extraordinary science into life-changing therapeutics for patients living with cancer, visit or follow us on LinkedIn. SOURCE Accent Therapeutics, Inc. 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临床申请临床1期

2024-09-12

·GlobeNewswire-Health Care

Oncternal Therapeutics Announces Termination of its Clinical Studies and Exploration of Strategic Alternatives

SAN DIEGO, Sept. 12, 2024 (GLOBE NEWSWIRE) -- Oncternal Therapeutics, Inc. (Nasdaq: ONCT) (the “Company”) today announced its decision to discontinue its clinical trials evaluating ONCT-534, its dual action androgen receptor inhibitor for the treatment of patients with metastatic castration resistant cancer, and ONCT-808, its ROR1-targeting autologous CAR T program for the treatment of patients with aggressive B-cell lymphoma, and to explore strategic alternatives. In the current study, interim Phase 1 results of ONCT-534 did not show clinically meaningful improvements of disease, including prostate-specific antigen (PSA) levels, in the 20 patients treated in eight dosing cohorts with various doses and schedules of administration of ONCT-534. ONCT-534 was generally well tolerated, with dose limiting toxicity observed in 2 of 3 patients at the highest dose tested, 1200 mg given orally once per day. The results with ONCT-808 at an interim Phase 1 analysis showed anti-tumor activity at every dose tested, including a complete metabolic response lasting eight months and long-term persistence of the CAR-T cells, with expected treatment emergent adverse events for a CAR-T therapy, and one death due to complications of shock at the highest dose tested. Based on the available clinical data and capital requirements for continued development, the Company has decided to terminate these studies. The Company will focus on exploring strategic alternatives with the goal of maximizing value for its stockholders, which may include asset sales, licensing or other strategic transactions relating to the Company’s development programs or a merger, reverse merger, acquisition, or other business combination involving the Company. While this strategic exploration is ongoing, the Company will discontinue all product development activities and will take other steps to reduce costs, including a reduction in its workforce to preserve cash resources. “The early results during dose escalation in the Phase 1/2 studies of ONCT-534 in heavily pretreated patients are disappointing, as the study was supported by extensive preclinical data and was designed to address important unmet medical needs for patients with advanced prostate cancer,” said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. “In light of these data and the challenging financing environment, we intend to explore strategic options with the hope of advancing and realizing value from our pipeline including ONCT-534, ONCT-808, zilovertamab and ONCT-216.” About Oncternal TherapeuticsOncternal Therapeutics is a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies for the treatment of patients with cancers that have critical unmet medical need. Oncternal pursues drug development targeting promising, yet untapped biological pathways implicated in cancer generation or progression, focusing on hematological malignancies and prostate cancer. More information on our company and programs is available at https://oncternal.com/. About ONCT-534 ONCT-534 is an investigational dual-action androgen receptor inhibitor (DAARI) with demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR mutation and aberration. It is a potential treatment for patients with mCRPC with unmet medical need because of resistance to androgen receptor pathway inhibitors, including those with AR amplification, mutations in the AR ligand binding domain (LBD), or splice variants with loss of the AR LBD. It is being investigated in Study ONCT-534-101 (NCT05917470) for the treatment of patients with mCRPC who are resistant to current AR pathway inhibitors. About ONCT-808ONCT-808 is an investigational autologous chimeric antigen receptor T (CAR T) cell therapy that targets Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using the binding domain from zilovertamab. ONCT-808 has demonstrated activity in preclinical models against multiple hematological malignancies and solid tumors and has been shown to be specific for cancer cells expressing ROR1. Oncternal has developed a robust and reproducible manufacturing process that has the potential to reduce the time patients must wait for their individual CAR T therapy to be produced compared with currently approved CAR T products. Oncternal has dosed patients under Study ONCT-808-101 (NCT05588440) with relapsed or refractory aggressive B-cell lymphoma, including patients who have failed previous CD19 CAR T treatment. About zilovertamabZilovertamab (previously called cirmtuzumab and UC-961) is an investigational monoclonal antibody designed to inhibit the function of ROR1. Zilovertamab has been evaluated in Phase 1/2 Study CIRM-0001 (NCT03088878) in combination with ibrutinib for the treatment of patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL), which resulted in 100% progression free survival (PFS) at 48 months in CLL patients whose tumors harbored p53 mutation/del(17p), a population underserved by current treatment options. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to zilovertamab for the treatment of CLL and MCL. The results of an investigator-sponsored, Phase 1b clinical trial of zilovertamab in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer were recently published (Shatsky 2023). Zilovertamab is being evaluated in an investigator-initiated Phase 1b study of zilovertamab in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (NCT05156905), and an investigator-initiated Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory (R/R) CLL (NCT04501939). About ONCT-216ONCT-216 (previously called TK216) is an investigational targeted small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins including fusion proteins. Tumorigenic fusion proteins involving the EWS protein and an ETS protein can be found in most cases of Ewing sarcoma. ETS-related translocations or overexpression are also found in many other tumors such as acute myeloid leukemia (AML), diffuse large B cell lymphoma (DLBCL), and prostate cancer. In preclinical models, ONCT-216 was observed to bind to EWS-FLI1, blocking the interaction between this fusion protein and other transcriptome proteins such as RNA helicase A, leading to tumor cell apoptosis and inhibiting tumor growth in animal models. The U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease Designation, Orphan Drug Designation and Fast Track Status to ONCT-216 for the treatment of Ewing sarcoma. The results of a Phase 1/ 2 clinical trial of ONCT-216 in patients with Ewing sarcoma (NCT02657005) were recently published (Myers 2024). Forward-Looking Information Oncternal cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or “continue” or the negatives of these terms or other similar expressions. These statements are based on Oncternal’s current beliefs and expectations. Forward-looking statements include statements regarding: Oncternal’s ability to complete a strategic transaction or continue as a going concern even if a strategic transaction is completed; anticipated benefits of strategic transactions; and Oncternal’s ability to preserve cash during the strategic alternatives process. Forward-looking statements are subject to risks and uncertainties inherent in Oncternal’s business, including: Oncternal may not realize the benefits expected from the workforce reduction and discontinuation of product development activities, including its ability to conserve cash; Oncternal’s ability to retain remaining key personnel; whether Oncternal will be able to secure and complete or achieve the anticipated benefits from any potential strategic transactions on acceptable terms or at all; Oncternal may use its capital resources sooner than it anticipates, resulting in a liquidation and dissolution of the Company; Oncternal’s common stock may be delisted from Nasdaq; and other risks described in Oncternal’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements in this press release are current only as of the date hereof and, except as required by applicable law, Oncternal undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Contact Information: InvestorsRichard Vincent 858-434-1113rvincent@oncternal.com Business DevelopmentPablo Urbaneja 415-316-8276 purbaneja@oncternal.com

临床1期孤儿药临床结果快速通道临床2期