A Phase 2, Multicenter, Open Label Dose-ranging Study of Sepantronium Bromide in Patients With Relapsed/Refractory c-Myc Rearranged High-grade B-cell Lymphoma (HGBCL)

This is a multi-center Phase 2 study to determine the safety and efficacy of sepantronium bromide (SepB) in adult patients with relapsed or refractory high-grade B-cell lymphoma

开始日期2022-12-09

申办/合作机构-

NCT01100931 / Completed临床1/2期IIT

A Phase I/II Study of Paclitaxel, Carboplatin and YM155 (Survivin Suppressor) in Subjects With Solid Tumors (Phase I) and Advanced Non-Small Cell Lung Carcinoma (Phase II)

Background:
Carboplatin-paclitaxel is a commonly used chemotherapy combination for advanced non-small-cell lung carcinoma (NSCLC) and other solid tumors. In a randomized clinical trial, the combination of carboplatin, paclitaxel, and the additional chemotherapy drug bevacizumab had a better response rate and survival compared to carboplatin and paclitaxel alone. However, this trial treated only patients with a specific diagnosis and treatment risks. Further research is needed to determine whether this combination is useful for other diagnoses.
YM155 is a drug that targets a type of chemical often found in cancer cells. It has been investigated in several phase I and phase II clinical trials, and it has been shown to be well tolerated and moderately effective in treating advanced NSCLC in patients who had not responded well to one or two standard treatments.
Objectives:
- To determine the efficacy of the combination of carboplatin, paclitaxel, and YM155 in the treatment of non-small-cell lung cancer.
Eligibility:
- Individuals 18 years of age and older who have been diagnosed with advanced non-small-cell lung carcinoma or other solid tumors for which standard therapy is not likely to be effective.
Design:
Before the start of the study, participants will be screened with a medical history, blood tests, imaging scans of the affected areas, tumor biopsies, and other tests as directed by the study doctors.
Participants will be treated for six 21-day cycles, or 18 weeks of treatment. Each cycle will include blood tests and imaging studies as required.
On day 1 of each cycle, participants will receive an infusion of paclitaxel and carboplatin, followed by a 4-day infusion of YM155 (through a portable electronic infusion pump).
Participants will have a computed tomography scan or other imaging every other cycle (approximately every 6 weeks) to determine whether the therapy is affecting the cancer site.
After the sixth cycle, participants will return for follow-up visits at least every 3 months, and will be asked to remain in contact with the researchers to allow further study of the long-term effects of the treatment.

开始日期2010-02-01

申办/合作机构

National Cancer Institute

NCT01038804 / Completed临床2期

A Phase II, Multicenter, Open-Label, Randomized Study of YM155 Plus Docetaxel as First-Line Treatment in Subjects With HER2 Negative Metastatic Breast Cancer

The purpose of this study is to evaluate survival, response rate, safety and tolerability of YM155 given in combination with docetaxel as first-line treatment in subjects with human epidermal growth factor 2 non-overexpressing (HER2 negative) metastatic breast cancer.

开始日期2009-12-01

申办/合作机构

Astellas Pharma, Inc.

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100 项与 Sepantronium Bromide 相关的转化医学

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100 项与 Sepantronium Bromide 相关的专利（医药）

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项与 Sepantronium Bromide 相关的文献（医药）

2024-04-01·Apoptosis : an international journal on programmed cell death

Synergistic cytotoxicity of decitabine and YM155 in leukemia cells through upregulation of SLC35F2 and suppression of MCL1 and survivin expression

Article

作者: Chiou, Jing-Ting ; Chang, Long-Sen

The hypomethylation agent decitabine (DAC), in combination with other apoptosis inducers, is considered a potential modality for cancer treatment. We investigated the mechanism underlying the combined cytotoxicity of DAC and YM155 in acute myeloid leukemia (AML) cells because of increasing evidence that YM155 induces apoptosis in cancer cells. Co-administration of DAC and YM155 resulted in synergistic cytotoxicity in AML U937 cells, which was characterized by the induction of apoptosis, NOXA-dependent degradation of MCL1 and survivin, and depolarization of mitochondria. Restoration of MCL1 or survivin expression attenuated DAC/YM155-induced U937 cell death. DAC initiated AKT and p38 MAPK phosphorylation in a Ca²⁺/ROS-dependent manner, thereby promoting autophagy-mediated degradation of β-TrCP mRNA, leading to increased Sp1 expression. DAC-induced Sp1 expression associated with Ten-eleven-translocation (TET) dioxygenases and p300 was used to upregulate the expression of SLC35F2. Simultaneously, the activation of p38 MAPK induced by DAC, promoted CREB-mediated NOXA expression, resulting in survivin and MCL1 degradation. The synergistic cytotoxicity of DAC and YM155 in U937 cells was dependent on elevated SLC35F2 expression. Additionally, YM155 facilitated DAC-induced degradation of MCL1 and survivin. A similar mechanism explained DAC/YM155-mediated cytotoxicity in AML HL-60 cells. Our data demonstrated that the synergistic cytotoxicity of DAC and YM155 in AML cell lines U937 and HL-60 is dependent on AKT- and p38 MAPK-mediated upregulation of SLC35F2 and p38 MAPK-mediated degradation of survivin and MCL1. This indicates that a treatment regimen that amalgamates YM155 and DAC may be beneficial for AML.

2024-03-01·Environmental toxicology

Hypoxia‐based critical gene biomarkers as prognostic reporters for gastric adenocarcinoma

Article

作者: Liu, Yunfei ; Liao, Yin ; Wu, Ji ; Zuo, Hongbin ; Zhao, Peiyou ; Chen, Xinwei ; Zhang, Zhiya

Abstract:

Background:

Gastric cancer is the most common malignant tumour of the digestive system, yet there is a lack of reported prognostic biomarkers for STAD patients.

Methods:

Transcriptomic expression data of STAD from GEO database, single cell sequencing data from OMIX gastric cancer database. Conservative molecular typing of gastric cancer was constructed using non‐negative matrix factorization (NMF). The abundance of 28 immune cells in the tumour samples was assessed using ssGSEA. The R package “oncoPredict” was used to predict chemotherapy response. TIDE website for immunotherapy response prediction. Finally, single cell analysis was performed to clarify the specific type annotation of STAD cells and to analysis their spatial expression.

Results:

Hypoxia‐score demonstrated excellent prognostic discrimination in TCGA gastric cancer samples. Among multiple deconvolution‐based algorithms for immune infiltration, Hypoxia‐score presented a general immunosuppressive efficacy across multiple datasets, as evidenced by a broad negative correlation with immune cell infiltration. By the likelihood that each group may have specific drug sensitivity to multiple chemotherapeutic and targeted agents. Results showed that high‐risk scoring patients were more sensitive to Staurosporine, Sabutoclax, and AZD8055, while low‐risk patients were more sensitive to Bortezomib, Dactinomycin, Docetaxel, Daporinad, Sepantronium, and bromide. In the immunotherapy cohort, the Hypoxia‐score presented the ability to discriminate for immunotherapy efficacy. The distribution of Hypoxia‐score in single‐cell descending space was calculated using AddModuleScore and was found to be distributed across the various cell types annotated in the single‐cell analysis. It is suggested that various cells in the tumour microenvironment are involved in hypoxia gene set processes to varying degrees.

Conclusion:

The Hypoxia‐score proves to be a valuable tool for assessing the prognosis of gastric cancer patients and guiding drug treatments, providing significant guidance for clinical diagnosis and treatment in the context of gastric cancer.

Hepatology (Baltimore, Md.)

Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma

Article

作者: Wang, Ye ; Yu, Decai ; Liu, Qi ; Li, Huan ; Li, Binghua ; Xu, Yanchao ; Qian, Liyuan ; Mehal, Wajahat Z. ; Zhou, Huajun ; Lu, Jiaming ; Cao, Yajuan ; Zhang, Yuchen ; Xu, Zhu ; Guo, Sheng ; Xie, Yuanyuan ; Su, Ke ; Li, Yunzheng ; Zhang, Laizhu ; Peng, Jin ; Hu, Yue ; Lu, Yijun ; Cheng, Chunxiao

Background and Aims::

Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy.

Approach and Results::

We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies.

Conclusions::

We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.

项与 Sepantronium Bromide 相关的新闻（医药）

2024-08-31

·药精通Bio

深度长文 | 难成药靶点c-Myc征途漫漫

TIS2024第四届自免疾病细胞疗法与干细胞疗法论坛重磅来袭，点击图片查看重磅嘉宾，合作详询：王晨 180 1628 8769 （扫码立即报名获取TIS2024免费票）编者注：本篇为VVIP投稿~ 2022年11月11日，Nature Review Drug Discovery的一篇新闻稿“Climbing cancer’s MYC mountain”对Omomyc I期临床结果的报道，让靶向c-Myc的药物研发重回大众的视野[1]。图1：c-Myc/Max 异二聚体- E-box DNA的复合物结构[1] Myc蛋白（又称c-Myc）在70%的肿瘤中表达失调，靶向失调的Myc蛋白有广泛的治疗作用。Myc作为转录因子，是一种固有无序蛋白，单独的Myc蛋白没有稳定的构象和适合小分子结合的位点，也是难成药代表性靶点。Myc蛋白自身稳定性较差，只有结合Max后才具有稳定构象，形成Myc-Max复合物后（图1），与DNA上的E-box序列结合启动下游基因转录[2]。直接靶向Myc蛋白有一定难度，因此，除了直接靶向Myc通路的Myc-Max相互作用和抑制Myc-Max复合物与DNA的相互作用外，间接调控Myc上下游通路也是治疗Myc相关疾病的重要方法。今天我们就来细说一下这些具有不同modality的Myc抑制剂的研究进展，扒一扒哪些公司在挂羊头卖狗肉，蹭Myc的热点。目前已有三款药物进入临床研究（Omomyc/PC002/WBC100），多款药物处于临床前研发阶段，药物形式也多种多样，涉及小分子抑制剂、多肽、Protac、分子胶等。 Omomyc 作为本轮热点的“始作俑者”，不得不先说说Omomyc。Soucek教授将c-Myc leucine zipper域中四个极性带电残基（E/E/R/R）突变为中性氨基酸（T/I/Q/N）得到含有91个氨基酸的工程肽Omomyc（图2），Omomyc可以自身二聚，也可以结合内源性Myc，阻断Myc-Max复合物与DNA-Ebox的相互作用，同时Omomyc也能够结合Max蛋白，阻断Myc-Max的相互作用（图3），进而促进内源性Myc蛋白的降解，抑制Myc下游基因转录发挥治疗作用[2]。图2：Omomyc的序列 OMO-103是基于Omomyc衍生化的细胞穿膜肽，2021年4月启动了一项针对晚期实体瘤的I期临床试验，用以评估其安全性、PK及有效性（NCT04808362）。入组的病人包括胰腺癌、肠癌和非小细胞肺癌等实体瘤病人，剂量从0.48 mg/kg爬坡到9.72 mg/kg，每周一次注射给药，RP2D=6.48mg/kg。截至到2022.10.10，给药9周后进行CT扫描的12名患者中，有8例病人中初步看到有效性（SD，stable disease），DLT是胰腺炎，其他不良反应多与静脉输液相关，安全性目前可接受。另外，临床前研究中发现，在小鼠肿瘤模型中瘤内药物浓度比血液中高四倍，人体PK显示给药50h后在血液里仍能检测到OMO-103，推测药物在人肿瘤中停留的时间可能更长[3]。 Omomyc/OMO-103在不同实体瘤中初步验证阻断Myc功能发挥治疗作用（虽然最好疗效是SD），安全性良好，应用肿瘤范围广，但是目前单药的治疗效果不够亮眼，未来在更大入组人数的表现、寻找合适的biomarker和亚组人群寻找、联用其他药物的结果值得期待。当然，小分子Myc抑制剂能否达到类似的安全性和有效性还有待进一步验证。图3：Omomyc的可能作用机制[2] PC-002 图4：PC-002结构临床进展最快的PC-002，又叫Sepantronium bromide（图4），是Cothera Bioscience（科赛睿生物/智康博药）开发用于治疗Myc基因异常淋巴瘤/神经母细胞瘤/神经内分泌前列腺癌的药物。目前正在进行针对高级别B细胞淋巴瘤的二期临床研究（NCT05263583）。Sepantronium bromide原先由Astellas Pharma开发，代号是YM-155，已经停止肿瘤临床开发。据科赛睿生物官网介绍，“PC-002是科赛睿生物公司的核心产品，是针对MYC基因变异肿瘤的first-in-class小分子药物。PC-002通过独特的作用机制（MOA）靶向MYC蛋白降解，选择性诱导MYC依赖的肿瘤细胞凋亡。PC-002以其独特的机理，选择性地杀伤具有MYC基因变异的肿瘤细胞，因而有望成为治疗多种癌症的重磅产品”[4]。经过检索发现“Sepantronium Bromide是一种有效的survivin抑制剂，通过抑制Survivin启动子活性而发挥作用”。Survivin作为一种抗凋亡蛋白，通常在肿瘤细胞中过度表达，介导肿瘤细胞逃避细胞凋亡，是潜在肿瘤治疗靶点。而c-Myc可以调节Survivin的转录，促进肿瘤的存活[5]。PC-002暂无公开证据表明其能直接靶向Myc而发挥功能，仅从科赛睿生物披露的机制来说，PC-002间接促进Myc的降解，临床选择人群也是Myc基因异常的肿瘤。其官网公开PC-002适应症人群而隐藏了靶点信息，有蹭热点的嫌疑。另外，PC002的化合物专利已经到期（WO 2001060803），科赛睿生物申请了联用和生物标记物专利（CN115605227），保护了PC002联用细胞周期阻滞剂治疗Myc相关肿瘤的用途。其临床前管线中还有一款基于PC-002改造的全新分子PC-002p用于治疗MYC+的肿瘤，可能也是Survivin抑制剂，专利暂未披露。 WBC100 图5：WBC100结构 WBC100是浙大医学院和第二军医大学联合开发的雷公藤甲素的缬氨酸酯衍生物。雷公藤甲素的靶点较多，尚未完全研究清楚其抗肿瘤机制，能够抑制包括NF-κB、HSF1、MDM2等多种靶点，对多种肿瘤细胞具有较强的增殖抑制作用。杭州卫本药业拥有WBC100的全球权利，已列入开发管线（wb001），目前处于I期临床研究阶段（CTR20211600）。2022年的一篇Adv. Sci.及专利WO2021208787报道WBC100是一种口服Myc分子胶，靶向c-Myc的NLS1-Basic-NLS2区域，通过E3泛素连接酶CHIP介导的26S蛋白酶体途径降解c-Myc蛋白，诱导肿瘤细胞凋亡，对多种c-Myc过表达的血液瘤和包括PDAC、NSCLC、HCC及CRC在内的实体瘤细胞有增殖抑制作用。并在极低剂量（0.1mpk）抑制c-Myc过表达AML、胰腺癌和胃癌肿瘤生长[9]。笔者并不质疑WBC100能够直接/间接/共价/非共价靶向c-Myc，但是从其结构来看，更相信Myc只是WBC100发挥抗肿瘤作用微不足道的靶点之一。WBC100结构中多个不稳定环氧丙烷结构的体内安全性也需慎重考虑。 GT-19077/GT-19715 苏州开拓药业管线中有两款靶向Myc的药物。其中，GT-19077是小分子Myc-Max蛋白-蛋白相互作用抑制剂，GT-19715是c-Myc/GSPT1双靶点降解剂，已经在IND阶段。图6：开拓药业专利中代表性结构与来鲁华课题组筛选的Myc抑制剂[6]及结构相似性cIAP1配体[7] 推测GT-19077可能来源于专利（WO2021004391/ WO2022089556），为含有硼酸或硼酸酯类的小分子化合物（图6），其结构基础推测是北大来鲁华课题组虚拟筛选出来的PKUMDL-YC-1205[6]。PKUMDL-YC-1205是Fmoc/Trt保护的天冬酰胺，看起来很是奇怪的一个分子，开拓将其保护基和氨基酸部分进一步改造，获得硼酸或硼酸酯类化合物。但是仔细推敲这些小分子，又像是cIAP1的配体[7]。含有硼酸或硼酸酯的小分子抑制剂可能是通过共价靶向c-Myc上的特定氨基酸增强与c-Myc的结合而发挥作用。图7：开拓药业专利中代表性结构及分子胶CC-885/CC-90009结构 GT-19715可能来源于开拓药业的降解剂专利（CN115504963/WO2022268066），分析其结构，似乎是在抑制剂基础上再加上Cereblon配体获得，但看起来更像是在GSPT1分子胶CC-90009/885的尾巴上加上Fmoc的类似基团（图7），不知是GT-19715降解谱筛选到了GSPT1，还是在分子胶的研发过程中加上了Myc抑制剂的结构。对于GT-19715是分子胶还是降解剂，开拓在不同的会议中定义不同，猜测GT-19715结构可能是CN115504963中化合物A153。从抑制剂和降解剂结构上看，虽然是宣传靶向Myc蛋白，但是脱靶风险非常高，当然降解剂已经明确是c-Myc/GSPT1双靶点。从多次会议公布的临床前药效模型来看， GT19630 (DC50=1.5 nM / IC50= 0.33 nM in HL-60；GT19715是 GT19630的盐型) ip给药在HL-60异种移植模型中有效地降解GSPT1，同时完全降解c-Myc，并在低剂量0.3 mg/kg/bid时抑制肿瘤生长，未引起体重明显下降，显示出良好的治疗效果和安全性。 GSPT1降解剂CC-90009的临床适应症也是AML/MS，临床前CC-90009对包括HL-60细胞在内的多种AML细胞具有亚纳摩级别抑制活性[8]。所以，在AML模型中GT19715发挥抑瘤作用究竟是降解Myc还是GSPT1所导致，抑或降解两个蛋白的协同作用，值得进一步探讨，毕竟在细胞增殖抑制中协同作用并不明显。开拓官方在多次会议中也披露GT19715能够抑制前列腺癌LNCap和耐药模型22RV-1肿瘤生长，并且能够促进AR-V7降解。同时，GT19715能够抑制小细胞肺癌细胞增殖和肿瘤生长，并促进c-Myc和N-Myc的降解。同一款分子胶或降解剂，在低浓度下，能够在不同肿瘤中促进包括c-Myc/N-Myc/GSPT1/GSPT2/CK1 alpha /IKZF1/AR-V7等多个蛋白的降解，笔者对这样一款超越分子胶或降解剂降解范围的分子的安全性不禁担忧。另外，不同于其他蛋白，Myc与Max蛋白间相互作用被阻断后，稳定性变差而降解，GT19715究竟是通过抑制Myc-Max蛋白-蛋白相互作用还是通过泛素-蛋白酶降解系统发挥作用，抑或是共同发挥作用，也是值得进一步验证。但是从公开数据来看，加入蛋白酶体抑制剂MLN9708能够抑制GT19715对Myc的降解，似乎泛素化降解发挥了一定作用。 ICX-101 ICX-101是Incurix开发的一种口服小分子Myc抑制剂，阻断c-Myc-Max异二聚体与DNA-E-box结合。官网披露EMSA/转录组实验验证了ICX-101对Myc具有选择性。 Incurix是韩国国立癌症中心下属子公司，主要研究肿瘤相关转录因子。韩国国立癌症中心专利（WO2012093741/WO2018021810/WO2018021849）显示其结构可能如图8所示，化合物51/56对包括膀胱癌、前列腺癌、肺癌、乳腺癌、白血病、胰腺癌、结直肠癌等肿瘤细胞的增殖抑制在μM级别，在肺癌（NCI-H1299）、前列腺癌（DU145）模型中抑制肿瘤生长。目前正在进行GLP和生物标记物研究，计划于2022年底进行临床试验，当前检索官网，仍未见临床消息。图8：WO2018021849专利中代表性分子 IDP-121/IDP-410 IDP Pharma 开发了两款肽类Myc抑制剂，其中IDP-121靶向c-Myc用于治疗c-Myc驱动肿瘤。IDP-410靶向N-Myc用于治疗脑胶，IDP-410能搜索到的数据较少。 IDP Pharma专利WO2019048679中披露了靶向c-Myc的拟肽S09、S14、IDP-P1708160和IDP-P1708161用于治疗多发性骨髓瘤（优选S09）。这些拟肽以c-Myc的一段基序为基础，通过“订书肽”形式维持野生肽的α-螺旋结构，增加其体内稳定性，阻断c-Myc与Max间形成复合物发挥抗增殖作用。专利数据显示这些拟肽在多种多发性骨髓瘤（MM）细胞系中具有μM水平的细胞毒作用，强于小分子抑制剂10058-F4，可作为单一药剂或与其他药物联合使用。体内外与标准疗法地塞米松和硼替佐米或环磷酰胺的药物的三联治疗中表现出协同抗肿瘤作用。目前IDP-121处于IND申请阶段，相较于野生型序列，IDP-121提高了稳定性，但在多发性骨髓瘤模型中单药抑瘤效果较差，与地塞米松、硼替佐米或环磷酰胺的二联或三联疗法中显示出显著的增强效果，临床首选适应症可能会是联用标准疗法用于标准疗法治疗失败的多发性骨髓瘤。图9：专利WO2019048679中代表性结构 c-Myc 蛋白表达抑制剂由于 c-Myc 蛋白缺乏稳定的构象和适合的小分子结合口袋，理性设计直接结合Myc的抑制剂具有较高挑战性。因此，也有一些biotech另辟蹊径，从c-Myc的转录和翻译入手，如Arrakis Therapeutics有一款靶向c-Myc mRNA的小分子，通过抑制c-Myc蛋白的表达，从而阻断Myc的功能，目前该项目正处于lead发现阶段。 Anima Biotech同样有一款c-Myc mRNA调节剂，专利WO2022150316披露一系列含硫三环结构分子，能够在细胞水平抑制c-Myc蛋白的翻译，代表性化合物332对c-Myc 依赖性A549肿瘤生长具有显著较强的抑制作用（3 mg/kg twice weekly，ip），目前该项目也处于lead优化阶段。图10：专利WO2022150316中分子332 c-Myc降解剂针对Myc这一难成药靶点，直接靶向Myc很难获得高亲和力分子，因此基于弱结合的抑制剂开发降解剂似乎是一个思路。蛋白降解领域的两家先驱Arvinas和Nurix Therapeutics均有一款靶向Myc的药物在临床前研发阶段，目前暂无专利披露。开拓GT19715究竟是Protac还是PPI抑制剂，抑或是c-Myc的分子胶，也还是值得进一步验证。笔者有个小疑问，c-Myc蛋白或mRNA半衰期低于半个小时，抑制剂干扰Myc-Max的相互作用后即可使Myc蛋白不稳定，促进降解，而在此基础上设计降解剂的有何更深层次的考虑？其他小分子 10074-G5和10058-F4是最早一批通过实验筛选发现的直接结合c-Myc蛋白的小分子，也是经分子水平、细胞水平和体内药效验证的c-Myc直接抑制剂。虽然存在荧光或典型的PAINS结构，这些化合物在分子水平通过FP、STD-NMR、2D-NMR、EMSA、CD等结合或竞争性实验验证能够直接结合在c-Myc上，并且明确10074-G5结合在c-Myc的aa363-481，10058-F4结合在aa404-412区域。通过直接结合在c-Myc蛋白上，进一步阻断Myc-Max的相互作用及Myc/Max复合物和DNA的相互作用。在细胞水平，这些分子能够抑制c-Myc依赖性的细胞增殖，下调c-Myc的转录活性，使细胞周期阻滞在G0/G1期等。由于筛选得到分子活性和理化性质不佳，研究者对10074-G5和10058-F4系列进行了多轮改造，3jc48-3的靶标活性和细胞活性略有提高，但是在体内药效并未体现出较优的抗肿瘤效果。但10074-G5和10058-F4结构简单，分子量较小，可作为苗头化合物进一步优化。化合物MICMI-6/7也经过分子、细胞及体内药效的验证，但是体内抗肿瘤效果一般，从其结构来看，都具有较大的刚性平面，且质子化能力较强，假阳性概率较高，不太适合进一步优化。 KDJ-Pyr-9这类联芳环结构与10074-G5结合在相同c-Myc蛋白序列，通过阻断Myc/Max-DNA相互作用抑制下游基因转录及细胞增殖，但分子刚性太强，分子量过大，有待于进一步优化。 Mycro1系列分子是基于Myc/Max-DNA的FP方法筛选出的化合物，对Myc-Max蛋白-蛋白相互作用具有较强的抑制作用，但对其他转录因子如CEBP/CEBP等的选择性较差。 MYCi361/975是基于已知c-Myc抑制剂构建药效团虚拟筛选、并进一步优化获得的c-Myc抑制剂，结合位点与10074-G5类似，这类分子是目前验证的较为充分的Myc抑制剂，从靶点结合到细胞增殖抑制、周期阻滞、Myc蛋白降解、下游基因转录抑制，系统验证了分子功能。但是此类分子的溶解度极差，单药抗肿瘤活性不强，成药性较差，有待于进一步优化。 KSI-3716是通过EMSA筛选得到的干扰c-Myc-Max复合物与DNA相互作用的小分子，同样能够抑制c-Myc的转录活性、细胞增殖及诱导细胞周期阻滞。KSI-3716本身具有较强的心脏毒性，因此后续开发了WO2018021849专利结构类似的含硫类分子。 Insilico在JPM2023最新披露的管线中也有一款在研c-Myc抑制剂，用于治疗肝癌，目前还处于discovery阶段。纵观这些早期研究中的小分子，整体上在靶标水平的结合能力不强，都在μM级别，细胞水平对多种c-Myc驱动肿瘤细胞增殖有抑制作用，但活性也不高，多数分子的溶解度、稳定性等理化性质不佳，这些分子多以iv或ip方式给药研究体内药效，在不同的肿瘤模型中，虽然展现出一定的抑瘤作用，但是效果一般，并未见到能消退肿瘤，多数分子的成药性较差。总结 c-Myc在多种肿瘤中表达异常，应用前景广阔。目前c-Myc直接抑制剂和间接抑制剂的开发尚处于早期阶段，已经发现的小分子抑制剂的成药性差，不足以支撑临床研究，亟待发现成药性更优的抑制剂。无序蛋白的药物开发有很大困难，许多biotech/AI制药公司把c-Myc这类难成药靶点作为管线开发，利用自家的平台优势，挑战难成药靶点药物的开发，一定会推动c-Myc抑制剂的研究进展。不过换个角度来看，虽然c-Myc在70%的肿瘤中表达失调，但是异常表达的c-Myc是肿瘤的直接驱动因素还是肿瘤发生发展的一个表现？开发c-Myc抑制剂能否在临床上对多种c-Myc失调的肿瘤有治疗效果？c-Myc抑制剂开发的高难度是否与其临床价值所匹配？相信随着越来越多的企业开始关注c-Myc抑制剂的开发，上述问题终将得到解答。参考文献 [1] Mullard A. Climbing cancer's MYC mountain. Nat Rev Drug Discov. 2022 Dec;21(12):865-867. [2] Madden SK, de Araujo AD, Gerhardt M, Fairlie DP, Mason JM. Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc. Mol Cancer. 2021 Jan 4;20(1):3. [3]http://www.peptomyc.com/results-revealed-from-phase-i-clinical-trial-of-the-first-drug-to-successfully-inhibit-the-myc-gene-which-drives-many-common-cancers/ [4] http://www.zkbymed.com/Index/Index/zixuncont/id/133 [5] Haque R, Song J, Haque M, Lei F, Sandhu P, Ni B, Zheng S, Fang D, Yang JM, Song J. c-Myc-Induced Survivin Is Essential for Promoting the Notch-Dependent T Cell Differentiation from Hematopoietic Stem Cells. Genes (Basel). 2017 Mar 6;8(3):97. [6] Yu C, Niu X, Jin F, Liu Z, Jin C, Lai L. Structure-based Inhibitor Design for the Intrinsically Disordered Protein c-Myc. Sci Rep. 2016 Mar 2;6:22298. [7] Shibata N, Nagai K, Morita Y, Ujikawa O, Ohoka N, Hattori T, Koyama R, Sano O, Imaeda Y, Nara H, Cho N, Naito M. Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands. J Med Chem. 2018 Jan 25;61(2):543-575. [8] Surka C, Jin L, Mbong N, Lu CC, Jang IS, Rychak E, Mendy D, Clayton T, Tindall E, Hsu C, Fontanillo C, Tran E, Contreras A, Ng SWK, Matyskiela M, Wang K, Chamberlain P, Cathers B, Carmichael J, Hansen J, Wang JCY, Minden MD, Fan J, Pierce DW, Pourdehnad M, Rolfe M, Lopez-Girona A, Dick JE, Lu G. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood. 2021 Feb 4;137(5):661-677. [9] Xu Y, Yu Q, Wang P, Wu Z, Zhang L, Wu S, Li M, Wu B, Li H, Zhuang H, Zhang X, Huang Y, Gan X, Xu R. A Selective Small-Molecule c-Myc Degrader Potently Regresses Lethal c-Myc Overexpressing Tumors. Adv Sci (Weinh). 2022 Mar;9(8):e2104344. END 免责声明：本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。 TIS2024第四届免疫细胞疗法与干细胞疗法论坛重磅来袭，合作详询：王晨 180 1628 8769

临床结果AACR会议临床1期蛋白降解靶向嵌合体细胞疗法

2022-12-19

·BioSpace

Cothera Announces Dosing of First Patient in Phase 2 Clinical Trial to Test Its DUB Inhibitor PC-002 for the Treatment of High-Grade B-cell Lymphoma

San Francisco, December 19, 2022--Cothera Bioscience today announced that it has dosed the first patient with PC-002, a first-in-class deubiquitinase (DUB) inhibitor, in a global multi-center phase 2 clinical trial for the treatment of high-grade B-cell lymphoma with Myc rearrangement (NCT05263583). This is a single-arm, single-agent proof-of-concept trial designed to evaluate PC-002 in patients who are either resistant or refractory to prior treatments. The company also announced that a paper1 describing PC-002’s mechanism-of-action was accepted for publication in the European Journal of Pharmaceutical Science. PC-002 (also known as YM155, sepantronium bromide) is a first-in-class small molecule inhibitor of DUB, an enzyme family which removes ubiquitin from cellular proteins otherwise destined for degradation. By inhibiting a key DUB activity that stabilizes the Myc protein in cancer cells, PC-002 selectively induces Myc protein degradation and cell apoptosis in Myc-dependent tumors. As Myc is regarded as one of the most important yet “undruggable” cancer targets with increased expression in more than 50% of human cancers, PC-002 may potentially address multiple cancer indications involving Myc dysregulation. Dr. Alex Wu, Co-founder and CEO of Cothera Bioscience, commented: "We are excited to dose the first patient in this important proof-of-concept trial. DUBs are an emerging target family with broad potential in cancer and inflammation treatment. PC-002 is the most advanced clinical stage DUB inhibitor which works by accelerating the degradation of Myc oncoprotein and has great potential to treat cancers depending on high Myc activity. Myc-driven high-grade lymphoma is a highly malignant, life-threatening disease for which there is currently no good treatment. We look forward to validating the safety and efficacy of PC-002 through this trial, providing a new solution for improving the prognosis of patients with this devastating disease, and delivering a breakthrough in the treatment of Myc-driven tumors.” 1. Li et al. YM155 Inhibits Neuroblastoma Growth through Degradation of MYCN: A New Role as a USP7 Inhibitor, European Journal of Pharmaceutical Sciences (2022) doi: About Cothera Bioscience, Inc. Cothera Bioscience is a clinical stage biotech company developing therapeutics for previously undruggable oncology targets with high unmet medical needs. The company’s strength is in its clinically validated translational platform exploiting synthetic lethality and protein degradation pathways for cancer killing. It was formed by the core founding members of Crown Bioscience, a leading contract research organization specializing in translational oncology, together with veteran serial entrepreneurs from Silicon Valley. Proprietary i-CR® technology platform Cothera Bioscience developed a patented proprietary i-CR® technology platform, a powerful method for individualized drug screening and new drug development. The platform combines a high content screening system with conditional reprogramming of primary cultured tumor cells, which enables efficient and undifferentiated expansion of primary patient-derived tumor cells in vitro while preserving the tumor’s heterogeneity. Through collaboration with leading oncology medical centers, Cothera Bioscience carried out prospective clinical trials and demonstrated that the i-CR® system can effectively predict the actual clinical response of a drug, with potential to significantly improve the clinical efficacy and success rate in anticancer drug development. (Transl Oncol. 2021 Jan;14(1):100935). For more information, please visit or send email to: bd@cotherabio.com

临床2期

100 项与 Sepantronium Bromide 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
C-Myc重排B细胞淋巴瘤	临床2期	中国	海口科瑞华生物科技有限公司	2022-07-14
C-Myc重排B细胞淋巴瘤	临床2期	中国	北京智康博药肿瘤医学研究有限公司	2022-07-14
C-Myc重排B细胞淋巴瘤	临床2期	韩国	北京智康博药肿瘤医学研究有限公司	2022-07-14
C-Myc重排B细胞淋巴瘤	临床2期	韩国	海口科瑞华生物科技有限公司	2022-07-14
晚期非小细胞肺癌	临床2期	美国	National Cancer Institute	2010-02-01
HER2 阴性乳腺癌	临床2期	美国	Astellas Pharma, Inc.	2009-12-01
HER2 阴性乳腺癌	临床2期	比利时	Astellas Pharma, Inc.	2009-12-01
HER2 阴性乳腺癌	临床2期	捷克	Astellas Pharma, Inc.	2009-12-01
HER2 阴性乳腺癌	临床2期	德国	Astellas Pharma, Inc.	2009-12-01
HER2 阴性乳腺癌	临床2期	爱尔兰	Astellas Pharma, Inc.	2009-12-01

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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


NCT05263583 (ASH2023)	临床2期	C-Myc阳性高级别B细胞淋巴瘤	-	PC-002 (Sepantronium Bromide, or SepB)	膚蓋醖膚蓋鹽憲簾蓋窪(齋襯網築鏇廠構製憲願) = 淵構壓範簾窪壓構艱願簾鹹窪製構繭襯選願顧 (齋網構鹽觸壓選積艱遞 )	-	2023-12-09
NCT01007292 (Pubmed \| Leuk Lymphoma) 人工标引	临床2期	侵袭性 B 细胞非霍奇金淋巴瘤	41	YM155+Rituximab	選蓋齋蓋艱艱鬱醖醖願(糧願築艱繭艱願顧鑰蓋) = 鏇簾顧窪餘鏇夢繭鹽顧築蓋糧鏇鏇鏇蓋鬱顧顧 (鑰壓壓鏇鏇淵艱蓋襯膚 ) 更多	不佳	2016-08-01
ASCO2016	临床1期	EGFR突变的非小细胞肺癌	18	YM155 + Erlotinib	齋襯鏇願觸築蓋構積齋(顧範獵獵壓艱鹽鏇餘觸) = One patient receiving 4.8 mg/ m2/d Y developed a dose-limiting transient reversible grade 2 serum creatinine elevation 製壓鑰蓋顧窪蓋構鹹齋 (願蓋窪醖築窪鏇積觸鬱 ) 更多	积极	2016-05-20
NCT01009775 (Pubmed \| Cancer Med) 人工标引	临床2期	黑色素瘤	64	docetaxel+YM155	範選鏇醖糧鹽製壓廠淵(蓋齋齋觸夢網鏇艱齋鬱) = 淵獵鑰簾齋廠糧膚壓蓋窪鬱簾構觸鹹製壓鬱蓋 (積衊築齋夢廠築齋糧醖, 21.3 ~ 48.6) 更多	不佳	2015-05-01
NCT01100931 (Pubmed \| Ann Oncol)	临床1/2期	晚期非小细胞肺癌	42	Sepantronium Bromide	願鹹襯齋獵鹽夢衊願構(壓鬱築憲鏇窪糧顧觸積) = 衊艱鬱淵齋網淵範製網積餘範齋鑰顧範積艱積 (夢襯構願範觸鏇繭網築 ) 更多	-	2013-10-01
NCT01038804 (ASCO2013) 人工标引	临床2期	HER2 阴性乳腺癌一线 HER2 negative	101	docetaxel+YM155	獵窪鬱顧構築選齋醖艱(觸顧鹽糧窪遞艱餘遞憲) = 餘醖築範願餘築艱顧憲簾膚選鏇網築蓋窪齋蓋 (膚廠餘廠網憲壓醖壓鏇, 176 ~ 333) 更多	积极	2013-05-20
NCT01038804 (ASCO2013) 人工标引	临床2期	HER2 阴性乳腺癌一线 HER2 negative	101	docetaxel	獵窪鬱顧構築選齋醖艱(觸顧鹽糧窪遞艱餘遞憲) = 襯艱蓋積廠選衊衊獵遞簾膚選鏇網築蓋窪齋蓋 (膚廠餘廠網憲壓醖壓鏇, 202 ~ 433) 更多	积极	2013-05-20
E1611 (ASCO2012)	N/A	梅克尔细胞癌	-	YM155	積構夢壓遞範鑰淵壓憲(淵獵淵餘蓋簾衊淵餘獵) = 壓衊鬱網選艱窪蓋膚壓網願遞餘遞顧窪鏇鹽餘 (構顧齋鑰築膚願壓願鏇 )	-	2012-05-20
E1611 (ASCO2012)	N/A	梅克尔细胞癌	-	Bortezomib	積構夢壓遞範鑰淵壓憲(淵獵淵餘蓋簾衊淵餘獵) = 廠憲遞積襯築簾餘鹽鑰網願遞餘遞顧窪鏇鹽餘 (構顧齋鑰築膚願壓願鏇 )	-	2012-05-20
ASCO2012	临床2期	黑色素瘤	64	YM155 plus docetaxelYM155 plus docetaxel	網艱選鹹壓積鏇鑰淵鏇(鬱醖衊壓顧淵願鬱遞蓋) = 顧鹽鑰衊願蓋憲鏇襯鏇窪繭築獵鏇憲窪願鬱壓 (憲鏇構積壓遞鬱鏇蓋齋 ) 更多	不佳	2012-05-20
ASCO2009	N/A	弥漫性大B细胞淋巴瘤	43	YM155	壓憲鏇選繭蓋製獵窪鏇(醖鹹獵鬱膚窪範廠範窪) = 廠醖襯鬱壓窪網膚餘鹹蓋選構醖鏇願衊襯夢築 (壓獵積範選蓋醖齋鑰廠 ) 更多	-	2009-05-20
ASCO2007	临床1期	HR阳性/HER2低表达实体瘤	34	YM155	築鑰繭願窪鑰鑰築鬱鹽(餘憲鹹觸顧蓋繭鏇憲簾) = 憲顧願鹽繭繭鹹餘餘糧餘餘齋鹽鹹遞淵襯選顧 (觸製願鏇鬱憲遞窪窪選 )	-	2007-06-20