A Phase II Study of Sequential Bipolar Androgen Therapy and ZEN-3694 in Sequence With Enzalutamide + ZEN-3694 in Asymptomatic Patients With Metastatic CRPC: The COSMYC Trial (COmbined Suppression of MYC)

This research is being done to determine if receiving the combination of testosterone and ZEN-3694 followed by the combination of enzalutamide plus ZEN-3694 will decrease the size of tumors in patients with prostate cancer that has become resistant to castration and other therapies. The investigators also want to determine if dosing first with the combination of testosterone and ZEN-3694 may cause enzalutamide and ZEN-3694 to work more effectively.

开始日期2025-08-19

申办/合作机构

The Sidney Kimmel Comprehensive Cancer Center

[+2]

NCT06102902

/ Recruiting临床1期IIT

A Phase 1 Study of ZEN003694 (ZEN-3694) in Combination With Cetuximab and Encorafenib in Patients With Refractory BRAF V600E Metastatic Colorectal Cancer

This phase I trial tests the safety, best dose, and effectiveness of ZEN003694 in combination with cetuximab and encorafenib in treating patients with colorectal cancer that has not responded to previous treatment (refractory), that has come back after a period of improvement (relapsed), and that has spread from where it first started (primary site) to other places in the body (metastatic). ZEN003694 is a protein inhibitor that binds to BET proteins. When ZEN003694 binds to BET proteins, it disrupts gene expression. Preventing the expression of certain growth-promoting genes may inhibit proliferation of tumor cells that over-express BET proteins. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Encorafenib is an enzyme inhibitor. It inhibits pathways that are responsible for controlling cell proliferation and survival, which may lead to a decrease in tumor cell proliferation. Both cetuximab and encorafenib have been approved to treat cancer. Adding ZEN003694 to cetuximab and encorafenib may be more effective at treating patients with refractory metastatic colorectal cancer than giving the usual treatment (cetuximab and encorafenib) alone.

开始日期2024-06-05

申办/合作机构

National Cancer Institute

NCT06161493

/ Withdrawn临床1期IIT

Phase l Study of a BET Inhibitor, ZEN003694, Combined With a PARP Inhibitor, Niraparib in Patients With Metastatic or Recurrent Solid Tumors

This Phase I, open label, dose determining study of oral niraparib in combination with ZEN003694 given daily in 28-day cycles will enroll patients with metastatic or recurrent solid cancer. Dose escalation will follow the mTPI-2/Keyboard design. Eligible patients will receive therapy until disease progression or unacceptable toxicities are experienced.

开始日期2024-01-23

申办/合作机构

University of Pittsburgh

[+2]

100 项与 ZEN-3694 相关的临床结果

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100 项与 ZEN-3694 相关的转化医学

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100 项与 ZEN-3694 相关的专利（医药）

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项与 ZEN-3694 相关的文献（医药）

2024-04-17·Bioanalysis

An LC–MS/MS method for determination of the bromodomain inhibitor ZEN-3694 and its metabolite ZEN-3791 in human plasma

Article

作者: Feng, Ye ; Piekarz, Richard ; Synold, Timothy W ; Mahdi, Haider ; Beumer, Jan H

We have developed and validated a novel LC-MS/MS method for the simultaneous quantification of ZEN-3694 and its active metabolite ZEN-3791 in human plasma after protein precipitation. Stable isotope-labeled versions were used as internal standards. Chromatographic separation was achieved on a Kinetex C18 column using 0.1% formic acid in H₂O and 0.1% formic acid in MeOH as mobile phases. Detection was performed via positive electrospray ionization mode with multiple reaction monitoring. The assay exhibited linearity in the concentration range of 5-5000 ng/ml for both analytes. Intra- and inter-assay precision and accuracy were within ±11%. ZEN-3694 and ZEN-3791 recoveries were between 93 and 105%. This LC-MS/MS assay is an essential tool to study ZEN-3694 in an ongoing clinical trial (NCT04840589).

2022-06-01·Cancer gene therapy2区 · 医学

Combination of ZEN-3694 with CDK4/6 inhibitors reverses acquired resistance to CDK4/6 inhibitors in ER-positive breast cancer

2区 · 医学

Article

作者: Kharenko, Olesya A ; Patel, Reena G ; van der Horst, Edward H ; Calosing, Cyrus

CDK4/6 inhibitors significantly prolong progression-free survival in patients with advanced hormone receptor-positive (HR+) HER2-negative breast cancer. Despite recent successes, patients acquire resistance, necessitating the development of additional novel therapeutic strategies. Bromodomain and extra-terminal domain (BET) proteins are key epigenetic regulators that interact with acetylated lysine (AcLys) residues of histones or transcription factors. BET proteins are directly involved in modulating estrogen receptor (ER) signaling and the cell cycle. Therefore, BET inhibitors can potentially offer new strategies in the treatment of advanced ER+ breast cancer. ZEN-3694 is an orally bioavailable small molecule BET inhibitor currently being evaluated in Phase 1/2 clinical trials (NCT03901469). To assess a potential combination strategy in a CDK4/6i resistant breast cancer population, we investigated the mechanism of action of ZEN-3694 combined with CDK4/6 inhibitors in the ER+ cell lines resistant to palbociclib or abemaciclib. Here, we describe that the combination of ZEN-3694 with CDK4/6i potently inhibits proliferation and induces apoptosis in CDK4/6i resistant cell lines. The resistance to both palbociclib and abemaciclib was associated with the strong upregulation of CDK6 and CCND1 protein levels, which was reversed by the ZEN-3694 treatment. Furthermore, RNAseq data and pathway analysis elucidated the combinatorial effects of ZEN-3694 with CDK4/6 inhibitors through significant downregulation of multiple pathways involved in cell cycle regulation, cellular growth, proliferation, apoptosis, inflammation, and cellular immune response. Our data indicate that ZEN-3694 has therapeutic potential in combination with CDK4/6 inhibitors in patients with advanced ER+ breast resistant to CDK4/6 inhibitors.

2020-10-15·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer

1区 · 医学

Article

作者: Campeau, Eric ; Aggarwal, Rahul R. ; Heath, Elisabeth I. ; Attwell, Sarah ; Bauman, Lisa ; Feng, Felix Y. ; Abida, Wassim ; Pantuck, Allan J. ; Nanus, David M. ; Schweizer, Michael T. ; Small, Eric J. ; Alumkal, Joshi J. ; Snyder, Margo ; Lakhotia, Sanjay ; Norek, Karen

Abstract:

Purpose::

ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods::

Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).

Results::

Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post–ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6–12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0–7.8). Median duration of treatment was 3.5 months (range, 0–34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).

Conclusions::

ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.

项与 ZEN-3694 相关的新闻（医药）

2025-08-04

·ioncology

腺启新疗丨转移性前列腺癌的新型靶点及治疗策略

点击上方蓝字关注我们编者按：随着对前列腺癌生物学机制与基因组特征的深入解析，一系列创新疗法应运而生：涵盖新型雄激素受体通路抑制剂（ARPI）、紫杉烷类化疗药物；以及基于分子分型的精准靶向治疗，包括聚腺苷二磷酸核糖聚合酶（PARP）抑制剂、程序性死亡蛋白1/程序性死亡配体1（PD-1/PD-L1）免疫检查点抑制剂及放射性核素标记的前列腺特异性膜抗原（PSMA）靶向药物177Lu-PSMA-617等。本文系统梳理了当前前列腺癌治疗领域的前沿策略，整合了全球范围内正在开展的重要临床试验最新数据。前列腺癌的新型治疗药物及其相关通路尽管临床诊疗已取得显著突破，但前列腺癌仍是导致全球男性癌症相关死亡的主要原因。作为一种激素依赖性肿瘤，转移性前列腺癌的早期系统治疗方案以雄激素剥夺疗法（ADT）联合ARPI为基础，并且多西他赛的用量正在逐步增加。然而，随着疾病进展，患者最终可能会发展为去势抵抗状态。当前获批用于转移性去势抵抗性前列腺癌（mCRPC）的治疗手段逐步多样，涵盖ARPI类药物、作用于微管结构的紫杉烷类化疗药物、基于放射性核素的靶向治疗（如镭-223及177Lu-PSMA-617），以及为携带同源重组修复缺陷（HRD）患者提供显著生存获益的PARP抑制剂。尽管如此，现阶段mCRPC患者的中位总生存期仍低于5年，这一严峻现实充分表明该领域亟待开发创新性的治疗策略。 △ 前列腺癌相关的分子靶向通路 △ 晚期前列腺癌的免疫治疗策略靶向持续性的雄激素受体（AR）通路 AR通路在前列腺癌生物学中依然至关重要，支持细胞存活、增殖和耐药性。虽然ADT和ARPI可以提高转移性前列腺癌的生存率，但耐药性的产生机制多种多样，通常都集中在AR信号通路增强上，包括配体生物合成增强、AR扩增、AR剪接和AR激活突变，以及AR非依赖性机制。靶向持续性AR信号传导仍然是治疗的重点；由于抗肿瘤活性有限，交叉耐药性限制了目前可用的靶向配体结合域（LBD）的ARPI。未来的治疗策略需要更优的化合物、用于检测AR-SV的预测性生物标志物（例如循环肿瘤细胞蛋白表达），以及针对共存耐药途径（例如PI3K/Akt/mTOR）、表观遗传学改变和疾病异质性）的合理组合。通过E3泛素连接酶靶向降解AR的策略也在研究中，但主要针对AR结合域。Bavdegalutamide可降解野生型和突变型AR，对AR突变的mCRPC具有抗肿瘤活性（PSA下降50%：46%，PSA下降30%：58%）；AR降解剂ARV-766的1/2期临床试验正在进行，该药物对某些Bavdegalutamide无效的AR突变具有活性。另一种AR降解剂和拮抗剂BMS-986365在一项针对mCRPC的1期临床试验中，在ARPI联合紫杉醇治疗后，也表现出PSA应答，放射学无进展生存为6.3个月（PSA50为50%）。不良事件（AE）包括QTc延长（47%，9%为3级），可通过降低剂量进行控制。一项针对mCRPC的3期临床试验正在比较BMS-986365与另一种ARPI或多西他赛。初步研究表明，AR突变的前列腺癌病例AR-SV表达较低，这可能解释了AR降解剂的抗肿瘤活性。阻断持续AR信号通路的替代策略是抑制CYP11（CYP17上游）；CYPIDES 1/2期临床试验评估了opeveostat（CYP11A1抑制剂）用于既往疗效不佳mCRPC患者的疗效。AR-LBD突变阳性患者的PSA50为53.0%，突变阴性患者的PSA50为14.7%，AR-LBD突变病例的客观缓解率（ORR）为18.6%。皮质类固醇可阻断肾上腺睾酮合成，但也可能导致雄激素受体（AR）突变，包括L702H突变，从而促进ARPI耐药性。糖皮质激素受体（GR）和AR均为核激素受体，由于存在许多共同的DNA反应元件，使得GR信号通路能够补偿AR抑制并影响ARPI敏感性。在AFFIRM恩扎卢胺试验中，皮质类固醇的使用与OS和rPFS缩短相关。此外，GR/AR比率低的患者PSA无进展生存（PFS；46% vs 22.4%）、rPFS（28.9% vs 10%）和OS（75.2% vs 48%）均优于比率高的患者。进一步的研究应制定选择性靶向肿瘤细胞中GR的策略，并考虑选择肿瘤表达高GR但缺乏AR-SV的患者。微生物菌群可能通过将雄激素前体转化为雄激素代谢物而导致 ARPI 耐药性；一项I期临床试验正在研究通过微生物组重塑来应对这一问题。 AR信号通路也可以通过靶向转录共激活因子和染色质调节因子来破坏，包括BET BRD2/3/4、P300组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDAC），从而影响前列腺癌基因组和表观遗传异常。HDAC抑制剂已证明具有临床前mCRPC抗肿瘤活性并与ARPI具有协同作用，需要进行临床评估。 BET和P300抑制剂可以阻断AR和AR-SV信号通路。BET抑制剂，包括 molibresib、birabresib和ZEN-3694，在临床试验中表现出有限的抗肿瘤活性、较窄的治疗窗口和血液学毒性，从而限制了其发展。P300阻断有助于逆转ARPI耐药性，选择性P300降解剂正在接受评估。另一种利用高AR表达的新策略是RIPTAC，目前正在进行临床评估，它能将AR和一种必需的细胞蛋白募集到稳定的三元复合物中，抑制必需蛋白的功能，导致AR阳性前列腺癌细胞死亡。靶向PI3K/AKT/PTEN信号 PI3K/AKT/PTEN通路在前列腺癌中由于PTEN缺失而频繁激活，与预后不良相关。针对p110α/β和AKT的靶向治疗仍在临床研究中。PI3K/AKT/mTOR和AR通路之间存在相互作用，其中AR抑制可增强AKT信号通路，使该通路成为关键的治疗靶点。在3期IPATential150试验中，ipatasertib联合阿比特龙治疗PI3K/AKT激活异常的mCRPC患者，其rPFS获益极小（2个月），且无OS获益。此外，最近的一份新闻稿报道称，多西他赛联合AKT抑制剂capivasertib治疗ARPI进展后mCRPC的3期试验因被认为不太可能达到其主要终点而提前终止。一项3期临床试验正在评估capivasertib联合阿比特龙治疗PTEN缺陷mHSPC的效果。近期发布的新闻稿称，该试验已达到其主要终点，即与安慰剂/阿比特龙组相比，患者rPFS有所改善。优化生物标志物（例如ctDNA分析以检测PI3K/AKT通路突变）并了解同时发生的分子改变的影响，可能有助于改善未来的患者选择。鉴于PTEN缺失会导致患者对这些疗法产生耐药性，目前正在探索联合治疗策略，包括AKT抑制剂联合DNA损伤反应药物、MCL-1抑制剂或免疫疗法。 CDK4/6抑制剂雄激素至少部分通过上调细胞周期蛋白D来促进前列腺癌生长。细胞周期蛋白D与CDK4/6结合，磷酸化Rb，释放E2F，从而驱动细胞周期进程；CDK4/6还能增强AR转录活性。CDK4/6抑制剂已被批准用于治疗HR+、HER2-乳腺癌。RB1缺陷或细胞周期蛋白E过表达的肿瘤对这些疗法无反应。一项针对RB1完整的新发mHSPC的ADT±哌柏西利的2期临床试验未能改善PSA反应或PFS。一项关于多西他赛、泼尼松和瑞波西利的1/2期临床试验显示，mCRPC患者的中位rPFS为8.1个月。Abemaciclib用于既往治疗且未进行RB1筛选的mCRPC患者，结果未达到其主要终点ORR。CYCLONE 2/3试验评估了abemaciclib联合阿比特龙/泼尼松用于一线治疗mCRPC和高危mHSPC，结果显示无生存获益，但并未进行RB1筛选。未来应探索分子学定义的亚组中潜在的疗效信号，以确保有希望的治疗途径不会被过早排除。靶向非AR驱动的mCRPC TP53和RB1的缺失与mCRPC中的AR独立性和谱系可塑性相关，这常见于治疗过程中出现的神经内分泌前列腺癌（NEPC）。在转移性前列腺癌中，TP53（突变或拷贝丢失）或RB1（主要是拷贝丢失）的双等位基因失活分别发生在约40%~50%和约12%的病例，在约4%的病例中两个基因均丢失。Rb通过CDK4/6调节G1期到S期的进展，其缺失可导致对内分泌治疗、靶向治疗和CDK4/6治疗的耐药性，部分作用于E2F/EZH2/NSD2轴。这催生了针对复制压力的策略，包括铂类和核苷类似物等细胞毒药物；拓扑异构酶、ATR或CDC7抑制剂；以及Aurora-A激酶（AURKA）。针对与谱系可塑性相关的表观遗传变化，支持了针对EZH1/2以及最近的NSD2的药物开发策略。 1. Aurora激酶抑制剂 NEPC与小细胞肺癌具有相似的组织学和分子学特征，预后较差，其特征是AURKA和N-Myc过表达，AR信号传导降低，PSA和PSMA水平降低。Alisertib（AURKA抑制剂）在转移性NEPC II期临床试验中显示出中等疗效，6个月rPFS率为13.4%，中位OS为9.5个月。本研究未使用RB1缺失或AURKA扩增等生物标志物筛选。 2. CDC7 CDC7是一种在复制应激下对DNA复制和修复至关重要的激酶，据报道，其在NEPC中存在依赖性。CDC7抑制剂simurosertib正在进行临床试验，主要毒性为中性粒细胞减少症。其他针对复制应激的策略包括抑制DNA修复基因，包括Wee1和ATR激酶。这些研究迫切需要预测性生物标志物。 3. EZH2 E2F信号增强驱动EZH2（也可能是EZH1）功能；这会影响包括染色质修饰在内的生物学变化。EZH2可以通过非经典功能驱动AR信号传导并调节谱系可塑性，EZH2抑制可使细胞对ARPI重新敏感。评估EZH2抑制剂（包括PF-06821497）与ARPI联合作用的试验正在进行，III期临床试验正在进行中。选择性EZH2抑制剂Mevrometostat在转移性去势抵抗性前列腺癌（mCRPC）的阿比特龙联合化疗后进行的I期临床试验显示，与恩扎卢胺联合使用可使疾病进展或死亡率相对降低49%，相当于中位rPFS延长8个月。该组合疗法可耐受（≥3级AE为53.7%，而单独使用恩扎卢胺则为42.5%）。 4. 靶向DNA修复缺陷和PARP抑制剂 PARP抑制剂是DNA修复的关键；HRD肿瘤依赖于PARP活性，因此易受PARP抑制剂的影响。BRCA1/2、PALB2和其他HR基因的缺失会导致对这些药物敏感，目前这些药物已成为HRD mCRPC的标准治疗方案。PROPEL、MAGNITUDE和TALAPRO-2三期临床试验表明，PARP抑制剂和PARP抑制剂在mCRPC患者中显著延长了rPFS，对BRCA2双等位基因缺失的肿瘤疗效最大，而对非HRD肿瘤疗效有限。多项试验正在测试PARP抑制剂的单独或联合用药效果。人们仍然担心，在早期疾病中长期使用PARP抑制剂会导致造血祖细胞DNA损伤，从而引发继发性血液系统恶性肿瘤。开发PARP1选择性抑制剂的努力已证明其疗效有限，并降低了血液学毒性。联合用药策略包括追求对DNA损伤剂的增敏，包括携带免疫偶联物和放射性核素的拓扑异构酶抑制剂，以及与PolQ抑制剂的合理联合用药，以防止BRCA逆转突变的出现，从而避免BRCA突变携带者产生耐药性。靶向细胞表面蛋白 △ 目前正在研究的前列腺癌表面靶蛋白具体可分为靶向PSMA的放射性配体（177Lu-PSMA-617、225Ac-PSMA-617等），以及靶向前列腺癌细胞表面蛋白的抗体偶联药物，这些蛋白包括PSMA、滋养层细胞表面抗原2（Trop-2）、组织因子、前列腺六跨膜上皮抗原1、人表皮生长因子受体2和3、B7-H3、Nectin-4等。免疫疗法免疫检查点抑制剂对晚期前列腺癌的疗效有限。帕博利珠单抗单药治疗在PD-L1阳性患者中的ORR为5%，在PD-L1阴性患者中的ORR为3.5%，中位OS分别为9.5个月和7.9个月。III期临床试验KEYNOTE-921（帕博利珠单抗/安慰剂+多西他赛）未能改善rPFS和OS，而帕博利珠单抗联合ARPI或PARPi治疗在非选择性mCRPC患者中也未显示出获益（KEYNOTE-641、KEYNOTE-991和KEYLYNK-010）。阿替利珠单抗单药治疗或联合恩扎卢胺治疗的结果同样令人失望。CONTACT-02 试验（卡博替尼+阿特珠单抗 vs ARPI换药）结果显示PFS延长2 个月（风险比0.65），但OS无获益。伊匹木单抗+纳武利尤单抗也显示出较低的ORR和PSA缓解率。据报道，镭-223可增强mCRPC患者的免疫原性和PD-L1表达，但在一项II期试验中，添加帕博利珠单抗并未增加配对骨活检中的CD4+/CD8+ T细胞浸润，并且在未选择生物标志物的人群中未显示rPFS或OS改善。其他放射性配体与免疫检查点抑制剂联合疗法正在接受评估。 ▌参考文献： Cimadamore A, Boixareu C, Sharp A, et al. Novel Therapeutic Strategies for Metastatic Prostate Cancer Care[J]. European Urology, 2025. 推荐阅读 1 腺启新疗丨前列腺癌细胞表面的哪些蛋白可以成为治疗靶点？目前有哪些新型药物？ 2 腺启新疗丨前列腺癌的免疫治疗机制及新探索（来源：《肿瘤瞭望-泌尿时讯》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

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·CPHI制药在线

晶锐医药可入脑的BET抑制剂获批临床，拥挤赛道是否还有突围机会

关注并星标CPHI制药在线近日，中国国家药监局药品审评中心（CDE）官网公示，晶锐医药1类新药JRD-018片获批临床，拟开发治疗晚期恶性肿瘤。 JRD-018是一款可入脑的BET抑制剂，今年4月已经获美国FDA批准开展1期临床研究。晶锐医药拟开启1期临床试验并将针对晚期实体瘤患者进行招募，继而扩展到血液瘤、脑转移或原发性脑瘤，旨在探索JRD-018在患者中的安全性、耐受性、药代动力学以及初步抗肿瘤活性。体内药效研究结果表明，JRD-018单独使用在脑胶质瘤模型、小细胞肺癌模型、非小细胞肺癌模型、髓性单核细胞白血病模型以及乳腺癌模型中均表现出良好的抗肿瘤活性。在临床前动物模型研究中，JRD-018已显示出良好的对脑转移或原发性脑瘤、恶性脑肿瘤的抑制效果。表观遗传学靶点之BET 溴结构域和超末端结构域（bromodomain and extra terminal domain，BET）属于溴结构域蛋白家族，BET蛋白家族包含四个异构体BRD2、BRD3、BRD4、BRDT，它们的结构相似，在N端有2个串联的溴结构域（BD1和BD2）以及一个超末端结构域（ET）。BD1和BD2识别并结合乙酰化赖氨酸残基，与染色质重塑和基因转录的调控过程相关；ET结构域与多种转录因子相互作用。BET蛋白家族通过溴结构域与乙酰化的染色质结合，从而实现在表观遗传学水平上对基因表达进行调控。 BET蛋白家族在人体内表达广泛，与多种实体瘤和恶性血液性肿瘤、炎症、肥胖、肺纤维化等多种疾病的发生和发展密切相关。如原癌基因Myc在超过一半的肿瘤中过表达，BET抑制剂通过竞争性结合阻止BRD4与染色质结合，进而抑制Myc的转录，从而实现抑制肿瘤的目的。 BET抑制剂是一类新型抗癌药，这类药物在治疗血液癌症如白血病和淋巴瘤方面具有良好的前景。BET抑制剂能够通过阻断BET蛋白的功能从而抑制肿瘤生长。研发BET蛋白选择性抑制剂是目前的新方向。目前，一系列BET抑制剂正在临床试验中检验它们治疗包括白血病、淋巴瘤、脑瘤和骨髓瘤在内的多种癌症的疗效。 BET抑制剂：诺华高调购入，加思科、正大天晴加速推进 BET被认为是抗肿瘤药物研发潜力靶点。目前，全球药企针对该靶点已开发出多款药物，详见下表。在研BET抑制剂大多为小分子化学药，此外还包括蛋白水解靶向嵌合体（PROTACs）。适应症上，BET抑制剂主要被开发用于实体瘤和血液性肿瘤，其中部分还被开发用于治疗炎症性疾病如白癜风等。全球至今还尚无BET抑制剂获批，进度最快的就是MorphoSys的Pelabresib，是首个三期临床试验取得成功的BET抑制剂。MorphoSys围绕该药物布局了骨髓纤维化、恶性外周神经鞘瘤、多发性骨髓瘤等多项适应症。 Pelabrisib是由MorphoSys AG公司研制的first-in-class BET抑制剂，近期Pelabrisib治疗骨髓纤维化III期达到了主要研究终点SVR35（脾脏缩小超过35%），从214例患者的临床数据来看， Pelabrisib与JAK抑制剂芦可替尼联用24周，有65.9%的患者脾脏缩小超过35%，而对照组（芦可替尼与安慰剂）仅有35.2%的患者达到SVR35，实验组的疗效比对照组高30.4%。今年年初，诺华以29亿美元收购MorphoSys AG从而拥有了pelabresib这款BET抑制剂。诺华将基于III期MANIFEST-2研究的积极数据在今年下半年向FDA和EMA提交pelabresib联合芦可替尼治疗骨髓纤维化的上市申请。 ZEN-3694是一种领先的差异化BET抑制剂，被开发联合免疫检查点抑制剂、PARP抑制剂、MEK抑制剂、CDK4/6抑制剂、HDAC抑制剂治疗多种肿瘤。ZEN-3694可以降低BRCA1/2和RAD51等蛋白的DNA修复活性，以提高肿瘤细胞对PARP抑制的敏感性，当前用以治疗转移性去势抵抗性前列腺癌II期临床正在开展中。2019年8月，Zenith Epigenetics 与恒翼生物就该药签订超7800万美元的许可协议，授权恒翼生物获得ZEN-3694在中国（包括中国香港、中国台湾和中国澳门地区）的权益。 JAB-8263是加科思自主研发、具有全球知识产权的小分子BET抑制剂，临床前研究显示其对多种实体瘤和血液瘤均能发挥抗肿瘤作用。从公开数据来看，JAB-8263是同类临床项目中活性最强的BET抑制剂，有望在极低剂量下有效抑制多种肿瘤生长，和Pelabrisib相比具有巨大的差异化优势。目前，加科思正在中美两地开展JAB-8263的多中心、开放性I/IIa期临床研究，适应症涉及白血病及实体瘤。 TQB3617是正大天晴自主研发的一款具有全新化学结构的BET抑制剂，能够通过抑制BET蛋白功能减少c-Myc、NF-κB、Aurora B和BCL-2等致癌基因的异常表达，进而发挥抗肿瘤作用。临床前研究结果显示，TQB3617对BET家族的BRD2、BRD3、BRD4、BRDT蛋白均具有较强的抑制活性。TQB3617用于晚期恶性肿瘤的I期临床试验显示，2例骨髓纤维化患者在治疗第12周结束时，脾脏体积较基线分别缩小13%和30%，展现出潜在的抗骨髓纤维化疗效。在28例接受疗效评估的淋巴瘤中，总缓解率（ORR）为39.3%（11/28），其中4例CR，7例PR。 Trotabresib（CC-90010）是一种新型、口服、可逆性、小分子BET抑制剂，可穿透高级别胶质瘤患者的脑肿瘤组织，临床前研究显示其可增强替莫唑胺（TMZ）的抗肿瘤作用。已公布的1b/2期开放标签、剂量探索研究结果显示：在长期随访中，新诊断胶质母细胞瘤（GBM）患者接受Trotabresib+TMZ辅助治疗或Trotabresib+TMZ+RT（放疗）同步治疗耐受性良好，未出现新的不良反应。结语整体来看，BET是进展相对较慢的一个表观遗传学药物靶点。BET蛋白家族在人体内表达广泛，与多种实体瘤和恶性血液性肿瘤、炎症、肥胖、肺纤维化等多种疾病的发生和发展密切相关，是非常有潜力的药物靶点，全球首个BET抑制剂pelabresib III期临床试验的成功宣告了该靶点的成效性，目前全球围绕BET靶点研发火热，值得一提的是，随着科学技术的发展，BET抑制剂的研发不再局限于小分子化药，已有多家企业、机构研发出BET靶向PROTACs。目前国内药企也积极布局BET靶点，而布局方式除了自主研发，还从外部企业引进，如恒翼生物。期待在药企的不懈努力下，BET靶点可以早日迎来重大突破。参考来源 1.Raajit Rampal, Sebastian Grosicki, Dominik Chraniuk et al.Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-na?ve patients with myelofibrosis.?JCO?42,?6502-6502(2024).DOI:10.1200/JCO.2024.42.16_suppl.6502 2.2024 ASCO. Abstract?#6502: Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-na?ve patients with myelofibrosis. END 来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

临床1期临床3期蛋白降解靶向嵌合体临床2期临床结果

2024-10-10

·PRNewswire

Metastatic Castration-Resistant Prostate Cancer Clinical Trial Pipeline Appears Robust With 90+ Key Pharma Companies Actively Working in the Therapeutics Segment | DelveInsight

Metastatic Castration-Resistant Prostate Cancer (mCRPC) refers to prostate cancer that has spread (metastasized) to other parts of the body and continues to progress despite treatments that lower testosterone levels (androgen deprivation therapy or ADT) major pharmaceutical companies are heavily investing in research and development of new treatments, including immunotherapy (e.g., sipuleucel-T) and targeted therapies, which are seen as the next frontier in treating mCRPC. The use of precision medicine to identify genetic profiles in patients has further expanded the potential for targeted treatment. LAS VEGAS , Oct. 10, 2024 /PRNewswire/ -- DelveInsight's ' Metastatic Castration-Resistant Prostate Cancer Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline mCRPC therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the mCRPC pipeline domain. Key Takeaways from the Metastatic Castration-Resistant Prostate Cancer Pipeline Report DelveInsight's mCRPC pipeline report depicts a robust space with 90+ active players working to develop 100+ pipeline therapies for mCRPC treatment. Key mCRPC companies such as Regeneron Pharmaceuticals, AstraZeneca, Hinova Pharmaceuticals, Zenith Epigenetic, Eli Lilly and Company, Astellas Pharma, Seagen, Pfizer, Progenics Pharmaceutical, Molecular Insight Pharmaceuticals, Bayer, Accutar Biotechnology Inc, Hinova Pharmaceuticals, Forma Therapeutics, Inc., HALDA THERAPEUTICS INC., Tavanta Therapeutics, Lantheus, Pfizer, AB Science, Syntrix Pharmaceuticals, Exelixis, Laekna Therapeutics Shanghai Co. Ltd., Cardiff Oncology, Ipsen, Norroy Bioscience, Astellas Pharma, Novartis, Johnson & Johnson, Tempest Therapeutics, and others are evaluating new mCRPC drugs to improve the treatment landscape. Promising mCRPC pipeline therapies such as REGN 4336, Capivasertib, Deutenzalutamide, ZEN003694, Abemaciclib, Enfortumab vedotin, Talazoparib, I-131-1095, Pelgifatamab corixetan, AC176, HP518, FT-7051, HLD-0915, TAVT-45, PNT2002, Mevrometostat, Masitinib, SX-682, XL092, LAE001, Onvansertib, Tazemetostat, 177Lu-NYM032, PRL-02, 225 Actinium PSMA 617, ARX51, TPST-1120, and others are under different phases of mCRPC clinical trials. In October 2024, Curium announced that it had entered into a strategic partnership with PDRadiopharma Inc, a wholly-owned subsidiary of PeptiDream, for the clinical development, regulatory filing, and commercialization in Japan of 177Lu-PSMA-I&T and 64Cu-PSMA-I&T. The two agents 177Lu-PSMA-I&T and 64Cu-PSMA-I&T target prostate-specific membrane antigen (PSMA) expressed on prostate cancer cells and are being investigated for prostate cancer treatment and diagnostics. In July 2024, the US FDA granted fast-track designation to the prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical 225Ac-FL-020 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). In July 2024, Merck and Orion Corporation announced the mutual exercise of option providing Merck global exclusive rights to Opevesostat, an investigational CYP11A1 inhibitor, for the treatment of Metastatic Castration-Resistant Prostate Cancer. In July 2024, the US FDA granted fast-track designation to the antibody-drug conjugate (ADC) BNT324/DB-1311 to potentially treat patients with unresectable advanced or metastatic castration-resistant prostate cancer (mCRPC) whose disease had progressed on or after standard systemic regimens. In July 2024, FutureChem announced that the FC-705 has received orphan drug designation from the Ministry of Food and Drug Safety (MFDS) for the treatment of prostate cancer. In June 2024, CAR T-Cell Therapy demonstrated promising results for mCRPC according to Phase I trial results. In January 2024, Lava Therapeutics announced that it has signed a clinical trial collaboration and supply agreement with Merck to evaluate its prostate cancer therapy LAVA-1207 as a combination treatment with MSD's Keytruda (pembrolizumab). In July 2024, Blue Earth Therapeutics announced the signing of a clinical research collaboration with University College London (UCL). The collaboration is centered on a Phase I/II trial designed to evaluate the safety, tolerability, radiation dosimetry, and antitumor activity of the 225Ac-rhPSMA-10.1 in men with metastatic castrate-resistant prostate cancer who have previously responded to lutetium 177 (177Lu)-PSMA therapy. Request a sample and discover the recent advances in mCRPC treatment drugs @ Metastatic Castration-Resistant Prostate Cancer Pipeline Report The mCRPC pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage mCRPC drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the mCRPC clinical trial landscape. Metastatic Castration-Resistant Prostate Cancer Overview Metastatic castration-resistant prostate cancer (mCRPC) is an advanced stage of prostate cancer that continues to grow and spread despite hormone therapy aimed at lowering testosterone levels. The term "metastatic" refers to cancer spreading to other parts of the body, such as the bones, lymph nodes, or distant organs, while "castration-resistant" indicates that the cancer no longer responds to treatments that reduce testosterone, a key driver of prostate cancer growth. mCRPC is typically more aggressive and challenging to treat than earlier stages of prostate cancer. The causes of mCRPC stem from genetic and environmental factors. Genetic mutations in the androgen receptor pathway can make cancer cells less dependent on testosterone, allowing them to thrive even under hormone-suppressing treatments. Environmental factors like diet, lifestyle, and exposure to certain chemicals may also contribute to the development and progression of prostate cancer. Symptoms of mCRPC often include pain in bones, fatigue, difficulty urinating, weight loss, and general weakness. As the cancer spreads, it can impair the function of other organs, depending on the site of metastasis. Diagnosis of mCRPC usually involves a combination of tests, including prostate-specific antigen (PSA) blood tests, imaging studies like CT scans, MRIs, or bone scans, and sometimes biopsies to confirm the spread and resistance to treatment. Treatment options for mCRPC are more complex and may include newer hormonal therapies (e.g., abiraterone, enzalutamide), chemotherapy (docetaxel or cabazitaxel), immunotherapy (e.g., sipuleucel-T), or targeted therapies such as PARP inhibitors. Bone-targeting therapies, radiation, and palliative care can also be used to manage symptoms and improve the quality of life. Treatment is typically tailored to the individual based on the extent of the disease and the patient health. Find out more about mCRPC treatment drugs @ Drugs for Metastatic Castration-Resistant Prostate Cancer Treatment A snapshot of the mCRPC Pipeline Drugs mentioned in the report: Learn more about the emerging mCRPC pipeline therapies @ Metastatic Castration-Resistant Prostate Cancer Clinical Trials Metastatic Castration-Resistant Prostate Cancer Therapeutics Assessment The mCRPC pipeline report proffers an integral view of the mCRPC emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Metastatic Castration-Resistant Prostate Cancer Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Intravenous, Subcutaneous Therapeutics Assessment By Molecule Type: Small molecule, Cell therapy, Peptides, Polymer, Small molecule, Gene therapy Therapeutics Assessment By Mechanism of Action: Androgen receptor degradation enhancers, Antibody-dependent cell cytotoxicity, Proto-oncogene protein c-akt inhibitors, Androgen receptor antagonists, Bromodomain and extraterminal domain protein inhibitors, Cyclin-dependent kinase 4 inhibitors, Cyclin-dependent kinase 6 inhibitors, Ionizing radiation emitters, PPAR alpha antagonists. Key Metastatic Castration-Resistant Prostate Cancer Companies: Regeneron Pharmaceuticals, AstraZeneca, Hinova Pharmaceuticals, Zenith Epigenetic, Eli Lilly and Company, Astellas Pharma, Seagen, Pfizer, Progenics Pharmaceutical, Molecular Insight Pharmaceuticals, Bayer, Accutar Biotechnology Inc, Hinova Pharmaceuticals, Forma Therapeutics, Inc., HALDA THERAPEUTICS INC., Tavanta Therapeutics, Lantheus, Pfizer, AB Science, Syntrix Pharmaceuticals, Exelixis, Laekna Therapeutics Shanghai Co. Ltd., Cardiff Oncology, Ipsen, Norroy Bioscience, Astellas Pharma, Novartis, Johnson & Johnson, Tempest Therapeutics, and others. Key Metastatic Castration-Resistant Prostate Cancer Pipeline Therapies: REGN 4336, Capivasertib, Deutenzalutamide, ZEN003694, Abemaciclib, Enfortumab vedotin, Talazoparib, I-131-1095, Pelgifatamab corixetan, AC176, HP518, FT-7051, HLD-0915, TAVT-45, PNT2002, Mevrometostat, Masitinib, SX-682, XL092, LAE001, Onvansertib, Tazemetostat, 177Lu-NYM032, PRL-02, 225 Actinium PSMA 617, ARX51, TPST-1120, and others. Dive deep into rich insights for new drugs for mCRPC treatment, visit @ Metastatic Castration-Resistant Prostate Cancer Drugs Table of Contents For further information on the mCRPC Cancer pipeline therapeutics, reach out @ Metastatic Castration-Resistant Prostate Cancer Treatment Drugs Related Reports Metastatic Castration-Resistant Prostate Cancer Market Metastatic Castration-Resistant Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key mCRPC companies including AstraZeneca, Merck Sharp & Dohme, Hinova Pharmaceuticals, Pfizer, Astellas Pharma, Modra Pharmaceuticals, AB Science, Eli Lilly and Company, Zr Pharma & GmbH, Bristol-Myers Squibb, Ipsen, Exelixis, Takeda, Janssen Research & Development, Tesaro, Lantheus Holdings, Kintor Pharmaceutical, MacroGenics, Daiichi Sankyo, Madison Vaccines, Novartis, Point Biopharma, Xencor, Essa Pharma, Telix International, Bayer, Arvinas, among others. Metastatic Prostate Cancer Market Metastatic Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key metastatic prostate cancer companies including AstraZeneca, Arvinas, Madison Vaccines, Phosplatin Therapeutics, Hinova Pharmaceuticals, Bristol Myers Squibb, Merck, MacroGenics, Daiichi Sankyo, Seagen, Taiho Pharmaceutical, Modra Pharmaceuticals, Xencor, Point Biopharma, Lantheus Holdings, Zenith Epigenetics, Essa Pharma, Telix Pharmaceuticals, Kintor Pharmaceutical, AB Science, Eli Lilly and Company, Exelixis among others. Metastatic Castration-Sensitive Prostate Cancer Market Metastatic Castration-Sensitive Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key mCSPC companies including Myovant Sciences, Pfizer, Bayer, Orion, Novartis, AstraZeneca, Pfizer, Janssen, Merck, Eli Lilly, among others. Metastatic Castration-Sensitive Prostate Cancer Pipeline Metastatic Castration-Sensitive Prostate Cancer Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, including clinical and non-clinical stage products, and the key mCSPC companies, including Myovant Sciences, Pfizer, Bayer, Orion, Novartis, AstraZeneca, Pfizer, Janssen, Merck, Eli Lilly, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

快速通道免疫疗法临床1期临床结果

100 项与 ZEN-3694 相关的药物交易

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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
输卵管癌	临床2期	美国	Pfizer Inc.	2023-04-21
输卵管癌	临床2期	美国	Zenith Epigenetics Ltd.	2023-04-21
原发性腹膜癌	临床2期	美国	Zenith Epigenetics Ltd.	2023-04-21
原发性腹膜癌	临床2期	美国	Pfizer Inc.	2023-04-21
复发性卵巢癌	临床2期	美国	Zenith Epigenetics Ltd.	2023-04-21
复发性卵巢癌	临床2期	美国	Pfizer Inc.	2023-04-21
复发性原发性腹膜癌	临床2期	美国	Pfizer Inc.	2023-04-21
复发性原发性腹膜癌	临床2期	美国	Zenith Epigenetics Ltd.	2023-04-21
晚期淋巴瘤	临床2期	美国	National Cancer Institute	2022-11-16
难治性B细胞淋巴瘤	临床2期	美国	National Cancer Institute	2022-11-16

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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


NCT03901469 (TNBC, CTgov)	临床2期	三阴性乳腺癌	115	Talazoparib+ZEN003694 (Expansion Cohort A - Combination Treatment in Post-TROP2-ADC Patients)	鬱築壓糧鹹選窪襯鏇範 = 膚範鏇範遞膚憲網糧齋鹹鬱鑰願繭鹽憲選糧築 (蓋憲夢憲糧積鬱齋鏇簾, 積願觸願構廠蓋鹹鑰艱 ~ 鹽簾蓋蓋鏇顧範鹽繭網) 更多	-	2025-10-07
NCT03901469 (TNBC, CTgov)	临床2期	三阴性乳腺癌	115	Talazoparib+ZEN003694 (Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve Patients)	網觸糧鏇襯壓齋獵構鹹 = 憲觸繭遞夢鹽顧觸鏇齋範遞廠壓鹽遞衊顧繭繭 (艱壓鑰膚蓋觸衊製鑰衊, 憲糧鹹淵廠襯憲艱顧獵 ~ 繭蓋膚壓觸蓋築鬱簾鏇) 更多	-	2025-10-07
NCT04471974 (ESMO2022) 人工标引	临床2期	转移性去势抵抗性前列腺癌 MSI-High	22	ZEN-3694+enzalutamide+pembrolizumab	遞淵蓋憲鏇獵淵繭憲鑰(夢襯積窪鏇蓋醖鑰窪衊) = ZEN 72 mg daily + ENZ 160 mg/day + P 200 mg IV q 3 weeks 構網鏇獵衊憲選醖顧窪 (淵齋鹽顧廠壓選鑰壓鑰 ) 更多	积极	2022-09-10
NCT03901469 (ASCO2022) 人工标引	临床1/2期	三阴性乳腺癌 ER Negative \| PR Negative \| HER2 Negative	51	ZEN-3694+talazoparib	艱鹽願齋鹽範鏇構艱醖(鑰鹹鏇醖鬱醖壓鑰膚鹹) = RP2D was determined to be 48mg qd ZEN-3694 plus 0.75mg qd talazoparib. 築鬱糧夢糧鹹夢鬱簾膚 (積餘獵壓艱觸鏇簾鏇鏇 ) 更多	积极	2022-06-02
NCT03901469 (ASCO2022) 人工标引	临床1/2期	三阴性乳腺癌 ER Negative \| PR Negative \| HER2 Negative	51	ZEN-3694+talazoparib (TNBC at diagnosis patients)		积极	2022-06-02
SABCS2021	临床1/2期	三阴性乳腺癌 wild-type BRCA1/2	15	ZEN003694 48mg + Talazoparib 1mg	蓋繭簾遞製窪淵憲積觸(衊餘鬱鹹積憲鏇齋壓鑰) = 鹽膚壓壓廠簾淵築鹽願憲壓艱獵廠蓋鹹壓獵獵 (襯廠憲願淵獵簾窪襯網 ) 更多	积极	2021-02-15
NCT02711956 (Pubmed \| Clin Cancer Res) 人工标引	临床1/2期	转移性去势抵抗性前列腺癌	75	Enzalutamide+ZEN-3694	襯鏇壓糧餘製鹹糧廠膚(壓製獵網選襯築蓋觸窪) = 繭網醖築夢顧窪顧繭淵膚網醖鹽餘鹹製網製簾 (衊憲獵願窪廠築壓鏇壓 ) 更多	积极	2020-10-15