Evaluation of Pyrrolone‐Fused Benzosuberene MK2 Inhibitors as Promising Therapeutic Agents for HNSCC: In Vitro Efficacy, In‐Vivo Safety, and Pharmacokinetic Profiling

Article

作者: Tavassoli, Mahvash ; Dhiman, Sumit ; Chhimwal, Jyoti ; Ahmed, Zabeer ; Padwad, Yogendra ; Das, Pralay ; Yamini ; Patial, Vikram ; Anand, Prince ; Nandi, Utpal

ABSTRACTMAPKAPK2/MK2 is well implicated in the progression of Head and Neck Squamous Cell Carcinoma (HNSCC), and potent MK2‐inhibitors are required to suppress its activity. Several MK2‐inhibitors have been developed in recent years to combat its effects on cancer. However, inadequate solubility, insufficient cellular permeability, systemic toxicity‐mediated side effects, and low bioavailability have severely impeded the advancement of MK2‐inhibitors to clinical trials. This void necessitates research to develop less toxic and more bioavailable potent MK2‐inhibitors in HNSCC. In the present article, we have evaluated the in‐vitro efficacy, in‐vivo single‐dose acute toxicity, and in‐vivo pharmacokinetic profiling of recently developed PfBS (pyrrolone‐fused benzosuberene) MK2‐inhibitor analogues against HNSCC. The PfBS MK2 inhibitor analogues impeded HPV+ and HPV‐ HNSCC cell proliferation and two‐dimensional migration. Moreover, MK2‐inhibitors lowered HNSCC cell clonogenic survival in a dose‐dependent manner, significantly enhancing radiation‐induced cell death via exerting radio‐sensitization effects. Furthermore, γ‐H2AX immunostaining revealed that PfBS analogues impaired DNA damage repair in HNSCC cells exposed to gamma radiation. In mice, PfBS MK2 inhibitors at 300 mg/kg were well‐tolerated without any lethal effects. Pharmacokinetic studies showed that PfBS analogues exhibited rapid absorption (Tmax), adequate plasma concentration above the micromolar level (C0 or Cmax), limited tissue distribution (Vd), and faster elimination from the body (Cl). Overall, this study summarizes in‐vitro efficacy, safety, and pharmacokinetics of developed MK2‐inhibitors and opens doors for pharmacodynamics and mechanism of action study of most effective leads in HNSCC.

2025-02-28·Biological and Pharmaceutical Bulletin

Stress Response Kinase MK2 Induces Non-canonical Activation of EphA2 in <i>EML4-ALK</i> Lung Cancer Cells

Article

作者: Zhang, Fang ; Zhou, Yue ; Sakurai, Hiroaki ; Matsumoto, Kunio ; Tanaka, Akihiro ; Yano, Seiji ; Mano, Hiroyuki ; Yokoyama, Satoru ; Hamada, Naru

The non-canonical phosphorylation of the receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) at Ser-897 plays crucial roles in tumor progression in a tyrosine kinase-independent manner. This phosphorylation is catalyzed by p90 ribosomal S6 kinase (RSK), a kinase downstream of extracellular signal-regulated kinase (ERK). We recently reported that stress-responsive kinase mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), instead of ERK, regulates RSK under cellular stress conditions; however, the function of MK2 in ERK-activated cells is still unknown. We herein clarified that MK2 regulates the RSK-EphA2 axis in ERK-activated echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) lung cancer cells. In addition, an MK2 inhibitor blocked enhancements in cell motility induced by the constitutively activated RSK-EphA2 axis. The present results reveal the importance of MK2 in the ERK-activated non-canonical activation of EphA2.

2024-12-09·Journal of Biomolecular Structure and Dynamics

Novel pyrrolone-fused benzosuberene MK2 inhibitors: synthesis, pharmacophore modelling, molecular docking, and anti-cancer efficacy evaluation in HNSCC cells

Article

作者: Yamini ; Kumar, Ashish ; Bhardwaj, Vijay Kumar ; Purohit, Rituraj ; Padwad, Yogendra ; Anand, Prince ; Das, Pralay

Head and neck Squamous Cell Carcinoma (HNSCC) is a growing concern worldwide and MAPKAPK2/MK2 (Mitogen-Activated Protein Kinase Activated Protein Kinase 2) is crucially involved in HNSCC progression. Increased disease burden and lacuna of targeted therapies require novel and safe pharmacological inhibitors to suppress the well-explored molecular targets in HNSCC. Here, we used dibromo-substituted benzosuberene synthesized from the mixture of α, β, γ-himachalenes and utilized as a precursor for the synthesis of Pyrrolone-fused benzosuberenes (PfBS) as MK2 inhibitors through aminocarbonylation approach in a single-pot reaction. The devised protocol provides a broad substrate scope, facile recovery, recyclability of Polystyrene-supported palladium (Pd@PS) nanoparticle catalyst, and fewer synthesis steps. In-silico molecular docking, pharmacophore modeling, and ADMET revealed MK2-inhibitory potential and drug-likeliness of PfBS analogues. Surface plasmon resonance (SPR) analysis revealed effective high binding affinity (K_D) and kinetics of PfBS analogues with MK2. Additionally, the SPR-mediated in-solution inhibition assay established the MK2-inhibition properties of PfBS analogues through abrogation of MK2-Hsp27 interaction. Further, in-vitro studies validate the findings in HNSCC cells. PfBS analogues exhibited significant anti-proliferative effects on CAL 27 tongue squamous carcinoma cells and were found safe on IEC-6 intestinal epithelial cells. Moreover, immunofluorescence analysis and western-blot assays potentiated, that selected analogues inhibited the inflammatory cytokine TNF-α induced activation of MK2 on cellular and molecular levels in HNSCC cells. In conclusion, this study presents novel MK2-inhibitors and opens the avenue for further pre-clinical and clinical efficacy evaluation of developed PfBS analogues in the treatment of HNSCC.Communicated by Ramaswamy H. Sarma.

项与 MK2抑制剂(恒瑞医药) 相关的新闻（医药）

2025-04-10

·转化医学网

索拉非尼耐药新机制！广州医科大学/中山大学合作发文:克服肝癌中索拉非尼耐药的新策略

4月8日，广州医科大学/中山大学研究团队合作共同在期刊《Advanced Science》上发表了题为“COPS5 Triggers Ferroptosis Defense by Stabilizing MK2 in Hepatocellular Carcinoma”的研究论文，本研究确定COPS5是肝细胞癌（HCC）中索拉非尼耐药的驱动因素以及铁死亡的抑制因子。机制上，COPS5 诱导热休克蛋白β-1（HSPB1）的激活，HSPB1 是铁死亡的抑制因子，从而保护 HCC 细胞免受铁死亡，最终导致索拉非尼耐药和肿瘤进展，而其自身表达可通过激活转录因子 4（ATF4）激活的转录由索拉非尼治疗诱导。此外，药理学抑制 COPS5/MK2 与索拉非尼协同作用诱导铁死亡并抑制 HCC 进展。该数据揭示了 COPS5 在肝细胞癌（HCC）中通过激活 MK2-HSPB1 轴在触发铁死亡防御和索拉非尼耐药性方面发挥的关键作用，并强调了靶向 COPS5/MK2 与索拉非尼联合治疗作为治疗 HCC 的有前景策略的潜力。 4月8日，广州医科大学/中山大学研究团队合作共同在期刊《Advanced Science》上发表了题为“COPS5 Triggers Ferroptosis Defense by Stabilizing MK2 in Hepatocellular Carcinoma”的研究论文，本研究确定COPS5是肝细胞癌（HCC）中索拉非尼耐药的驱动因素以及铁死亡的抑制因子。机制上，COPS5 诱导热休克蛋白β-1（HSPB1）的激活，HSPB1 是铁死亡的抑制因子，从而保护 HCC 细胞免受铁死亡，最终导致索拉非尼耐药和肿瘤进展，而其自身表达可通过激活转录因子 4（ATF4）激活的转录由索拉非尼治疗诱导。此外，药理学抑制 COPS5/MK2 与索拉非尼协同作用诱导铁死亡并抑制 HCC 进展。该数据揭示了 COPS5 在肝细胞癌（HCC）中通过激活 MK2-HSPB1 轴在触发铁死亡防御和索拉非尼耐药性方面发挥的关键作用，并强调了靶向 COPS5/MK2 与索拉非尼联合治疗作为治疗 HCC 的有前景策略的潜力。 https://advanced-onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/advs.202416360 https://advanced-onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/advs.202416360 研究背景研究背景 01 01 肝癌是全球最常见的恶性肿瘤之一，也是癌症相关死亡的第三大原因，2022 年有 757948 人（7.8%）死于肝癌。肝细胞癌（HCC）起源于肝细胞，是原发性肝癌的主要亚型，约占所有肝癌病例的 90%。对于早期肝细胞癌患者，推荐进行手术切除，而晚期肝细胞癌患者通常接受全身治疗，包括化疗药物和酪氨酸激酶抑制剂。索拉非尼是一种口服多激酶抑制剂，用于晚期肝细胞癌一线治疗的首个分子靶向药物，显著改善了部分患者的临床结局。另一种多激酶抑制剂仑伐替尼随后获批用于晚期肝细胞癌的一线治疗；然而，其总体生存率并未优于索拉非尼。尽管免疫疗法为肝细胞癌（HCC）的治疗开辟了新的策略，但只有少数患者对免疫疗法有反应。索拉非尼仍是晚期 HCC 的标准疗法，这得到了大量证据和临床经验的支持。但是，索拉非尼的总体反应率仅约为 30%，仅能将 HCC 患者的中位总生存期延长 2.8 个月。内在或获得性耐药是导致 HCC 患者索拉非尼治疗失败的主要障碍。肝癌是全球最常见的恶性肿瘤之一，也是癌症相关死亡的第三大原因，2022 年有 757948 人（7.8%）死于肝癌。肝细胞癌（HCC）起源于肝细胞，是原发性肝癌的主要亚型，约占所有肝癌病例的 90%。对于早期肝细胞癌患者，推荐进行手术切除，而晚期肝细胞癌患者通常接受全身治疗，包括化疗药物和酪氨酸激酶抑制剂。索拉非尼是一种口服多激酶抑制剂，用于晚期肝细胞癌一线治疗的首个分子靶向药物，显著改善了部分患者的临床结局。另一种多激酶抑制剂仑伐替尼随后获批用于晚期肝细胞癌的一线治疗；然而，其总体生存率并未优于索拉非尼。尽管免疫疗法为肝细胞癌（HCC）的治疗开辟了新的策略，但只有少数患者对免疫疗法有反应。索拉非尼仍是晚期 HCC 的标准疗法，这得到了大量证据和临床经验的支持。但是，索拉非尼的总体反应率仅约为 30%，仅能将 HCC 患者的中位总生存期延长 2.8 个月。内在或获得性耐药是导致 HCC 患者索拉非尼治疗失败的主要障碍。 MK2 抑制剂与索拉非尼联合使用可协同抑制肝细胞癌进展 MK2 抑制剂与索拉非尼联合使用可协同抑制肝细胞癌进展 02 02 研究人员研究了 MK2 抑制剂与索拉非尼联合治疗肝细胞癌（HCC）的疗效。如预期的那样，使用两种不同的 MK2 抑制剂，即 MK2 抑制剂 III 和 PF3644022，消除了基础和索拉非尼诱导的 MK2/HSPB1 磷酸化。MK2 的药理学抑制进一步增强了索拉非尼治疗诱导的细胞铁、脂质过氧化和丙二醛水平，导致线粒体形态改变。重要的是，HCC 细胞与 MK2 抑制剂和索拉非尼联合治疗导致了协同的生长抑制活性。为了进一步确定MK2 抑制剂和索拉非尼的协同作用，研究人员建立了患者来源的类器官（PDO）模型进行体外研究。索拉非尼与 MK2 抑制剂 III 的组合协同抑制了 HCC 类器官的生长。研究人员研究了 MK2 抑制剂与索拉非尼联合治疗肝细胞癌（HCC）的疗效。如预期的那样，使用两种不同的 MK2 抑制剂，即 MK2 抑制剂 III 和 PF3644022，消除了基础和索拉非尼诱导的 MK2/HSPB1 磷酸化。MK2 的药理学抑制进一步增强了索拉非尼治疗诱导的细胞铁、脂质过氧化和丙二醛水平，导致线粒体形态改变。重要的是，HCC 细胞与 MK2 抑制剂和索拉非尼联合治疗导致了协同的生长抑制活性。为了进一步确定MK2 抑制剂和索拉非尼的协同作用，研究人员建立了患者来源的类器官（PDO）模型进行体外研究。索拉非尼与 MK2 抑制剂 III 的组合协同抑制了 HCC 类器官的生长。 MK2 抑制剂与索拉非尼联合使用可协同抑制肝细胞癌的生长 MK2 抑制剂与索拉非尼联合使用可协同抑制肝细胞癌的生长随后，研究人员研究了索拉非尼与 MK2 抑制剂 III 的联合治疗。研究人员观察到，与单药治疗相比，索拉非尼与 MK2 抑制剂 III 的联合治疗对肿瘤负荷的抑制作用更为显著。此外，联合治疗显著延长了小鼠的生存时间，而单药治疗效果有限。研究还表明体内治疗耐受性良好。这些数据共同表明，索拉非尼与 MK2 抑制剂联合使用时具有协同抗肿瘤作用。随后，研究人员研究了索拉非尼与 MK2 抑制剂 III 的联合治疗。研究人员观察到，与单药治疗相比，索拉非尼与 MK2 抑制剂 III 的联合治疗对肿瘤负荷的抑制作用更为显著。此外，联合治疗显著延长了小鼠的生存时间，而单药治疗效果有限。研究还表明体内治疗耐受性良好。这些数据共同表明，索拉非尼与 MK2 抑制剂联合使用时具有协同抗肿瘤作用。结论结论 03 03 本研究为索拉非尼耐药性在 HCC 中的铁死亡相关机制提供了更深入的理解，并表明抑制 COPS5-MK2-HSPB1 轴是克服 HCC 中索拉非尼耐药性的潜在治疗策略。（转化医学网360zhyx.com）本研究为索拉非尼耐药性在 HCC 中的铁死亡相关机制提供了更深入的理解，并表明抑制 COPS5-MK2-HSPB1 轴是克服 HCC 中索拉非尼耐药性的潜在治疗策略。（转化医学网360zhyx.com）参考资料：参考资料： https://advanced-onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/advs.202416360 https://advanced-onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/advs.202416360 【关于投稿】【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。责任声明：本稿件如有错误之处，敬请联系转化医学网客服进行修改事宜！责任声明：本稿件如有错误之处，敬请联系转化医学网客服进行修改事宜！微信号：zhuanhuayixue 微信号：zhuanhuayixue

临床研究

2024-01-10

·FierceBiotech

Aclaris claims win for ‘soft’ JAK inhibitor but mixed data spooks investors

Investors sent Aclaris’ shares down 14% to $1.10 in pre-market trading. Aclaris Therapeutics has touted the latest phase 2 results for its “soft” JAK 1/3 inhibitor as a win for the beleaguered biotech, but investors appeared less enthusiastic about the wider set of mixed data. The phase 2b study involved 250 adults and children in the U.S. with mild to severe atopic dermatitis receiving either twice daily treatment with the therapy, called ATI-1777, as a spray at concentrations of 0.5%, 1% or 2%, or a once daily treatment of 2% or vehicle. At week four, the change in eczema from baseline as assessed by the Eczema Area and Severity Index (EASI) score was 69.7% for patients who received the 2% concentration twice daily compared with 58.7% for those who received the vehicle. The statistical significance of this difference, which equated to a p value of 0.035, met the trial’s primary efficacy endpoint, Aclaris said in a Jan. 10 release. However, while patients who received the once daily 2% concentration also saw a “trend toward significance”—with a 68.3% change compared to 59.5% among those receiving a vehicle—this was not “statistically superior,” the biotech admitted. Investors appeared dubious about the readout, sending Aclaris’ shares down 14% to $1.10 in pre-market trading from a Tuesday closing price of $1.28. While the trial had not been statistically powered for a response as measured by the Investigator Global Assessment Treatment Success, which the company noted is the FDA’s regulatory endpoint, Aclaris said the drug had shown improvement here as well, with changes of 37.2% and 36.6% for the once daily and twice daily 2% concentrations, respectively, compared to 27.1% and 26.3% in the respective vehicle cohorts. Aclaris did not share data on the efficacy of the 0.5% and 1% concentrations in the release. ATI-1777 had not produced any of the adverse events most commonly associated with JAK inhibitors, such as serious infections, malignancies, major adverse cardiovascular events or thromboses, according to the company. The most common adverse events among treated patients were nasopharyngitis and application site itch. “We are excited that ATI-1777 demonstrated response rates on par with existing market competition, along with a differentiated safety profile relative to JAK inhibitors given the low systemic absorption seen in both phase 2 studies,” Neal Walker, chairman of Aclaris’ board of directors, said in the release. “These results are particularly encouraging given the higher than anticipated vehicle response and the mid-study inclusion of a milder patient population,” Walker added. “The convenience of a spray formulation along with the potential to move to once-a-day dosing, potentially offer additional distinct advantages to patients suffering from atopic dermatitis.” Aclaris had been pinning its hopes on ATI-1777’s success after the company announced in the final weeks of the year that it was laying off almost half of its workforce as it resurrected plans to explore its MK2 inhibitor zunsemetinib despite a couple of mid-phase fails. At the time, Aclaris said that it would use a positive set of phase 2 data for ATI-1777 to hunt for a suitable partner for the asset.” In this morning’s release, the biotech’s CEO Douglas Manion, M.D., confirmed that the company would now “seek a development and commercialization partner for this program, which could include additional indications such as vitiligo.”

临床结果临床2期

2023-12-22

·佰傲谷BioValley

临床接连挫败后，裁员46%

主要候选药物在炎症性疾病中陷入死胡同后，美国生物技术公司Aclaris Therapeutics在本周二宣布，将裁员46%以节省资金，同时等待新的开发计划取得成果。据悉，截止2022年底Aclaris一共拥有100多名全职员工，此次裁员将在明年6月底之前完成。适应症全军覆没12月19日，公司发布的一份报告中，Aclaris首席执行官DouglasManion表示，裁员与其主要候选药物zunsemetinib（ATI-450）的开发进度不及预期有关。zunsemetinib是一种研究性口服MK2抑制剂。11月13日，Aclaris公布了zunsemetinib用于中度至重度类风湿性关节炎的2b临床试验结果。结果显示：给予20mg或50mg剂量的患者在12周时均未达到缓解的主要终点或任何次要疗效终点，在第12周时，zunsemetinib和安慰剂在任何疗效指标上均无显著差异。Aclaris表示将停止zunsemetinib所有的开发工作，包括银屑病关节炎的2期试验。“随着zunsemetinib用于免疫炎症性疾病的开发终止，我们希望采取措施来减少支出并精简公司的组织架构，我们希望可以尽可能的保存资本。”Manion说。事实上，11月的2期临床失败并不是zunsemetinib的第一次失败，Aclaris在3月份报告中说，在中度至重度化脓性汗腺炎（HS）的2a期研究（NCT05216224）中，该药物的结节和脓肿计数与基线相比没有显着变化。该研究也未能达到其次要终点，即化脓性汗腺炎临床反应（HiSCR-50）量表减少50%。当时Aclaris的股价直接腰斩至不到6美元，而11月的再次失败，让公司股价跌到不足1美元。回顾2023年初，zunsemetinib多达三个适应症的2b期临床在同时推进，包括类风湿性关节炎、化脓性汗腺炎和银屑病关节炎，可见Aclaris对这款药的重视。但是目前这三个适应症已经全部终止，宣布失败。财务状况Aclaris的2022年财报显示，截止2022年12月31日，Aclaris的现金、现金等价物和有价证券总额为2.298亿美元，包括与Pediatrix Therapeutics签订许可协议获得的受益。Aclaris还预计现金足够公司运营到2025年底。2022年，Aclaris总收入为2980万美元，净亏损为8690万美元，收入主要是来自专利许可协议，包括与礼来公司的非独家专利许可协议收到的1760万美元的预付款和里程碑付款，以及根据Pediatrix许可协议收到的500万美元预付款。亏损主要来自研发费用的增加，2022年，Aclaris研发费用为7780万美元，去年同期为4380美元。研发费用主要是候选药物Zunsemetinib、ATI-1777和ATI-2138的开发费用，以及员工人数增加而产生的薪酬相关费用。2023年第一季度财报显示，Aclaris的现金、现金等价物和有价证券总额为2.044亿美元，Aclaris仍然预计现金能支持公司运营到2025年底。但是进入2023年，由于研发费用的增加，亏损仍然在扩大，2023年第一季度净亏损为2820万美元，而2022年第一季度为1880万美元。研发费用为2260万美元，而去年同期为1430万美元。仅靠专利许可带来的收入，很难支撑多条临床管线同时烧钱，砍管线、裁员也是Aclaris的无奈之举。后续的希望虽然zunsemetinib的三种适应症几乎全军覆没，但是Aclaris还是决定再给zunsemetinib一次机会，在周二的新闻稿中，公司决定将继续探索zunsemetinib作为胰腺癌和转移性乳腺癌的潜在治疗方法，以及用来预防转移性乳腺癌患者的骨质流失。本来该适应症是其另外一款口服MK2抑制剂ATI-2231正在推进的，Aclaris联合华盛顿大学开展ATI-2231在晚期实体瘤恶性肿瘤患者中的首次人体1a期试验，但是公司认为zunsemetinib拥有更先进的临床开发包。此外，公司的外用JAK1/3抑制剂（ATI-1777）正在进行250例患者的2b期临床试验，这些研究对象包括轻度、中度或重度特应性皮炎患者，包括成人和年仅12岁的儿童。预计将在下个月公布最终结果。ATI-1777治疗中度至重度特应性皮炎（AD）的2a期试验结果发表在同行评审期刊JIDInnovations上。在2a期研究中，ATI-1777在治疗4周后显示出改良湿疹面积和严重程度指数的显着改善。Manion表示:“如果2b期试验的结果是积极的，我们打算为该资产寻求商业化合作伙伴。”Aclaris还有一款候选产品是口服共价ITK/JAK3抑制剂ATI-2138，该药在健康志愿者中进行的多次递增剂量研究显示出有希望的药代动力学和药效学特性，可能对T细胞介导的疾病产生积极影响。Aclaris原计划是在2024年初进行其用于治疗溃疡性结肠炎的2期试验。但是由于溃疡性结肠炎的市场竞争格局不断变化，Aclaris打算重新评估ATI-2138的最有效治疗途径——包括适应证的重新选择。这个竞争格局变化可能主要是指礼来，礼来的IL-23单抗Mirikizumab。10月26日，礼来宣布IL-23p19单抗Mirikizumab（商品名：Omvoh）获得FDA批准：用于治疗成人中至重度溃疡性结肠炎（UC）。Mirikizumab也成为首个获批用于治疗UC的IL-23抗体。2023年3月27日，该药物首次获得日本厚生劳动省（MHLW）批准上市，用于治疗溃疡性结肠炎。管线要么适应症临床失败，要么市场被竞争对手先行一步，裁员后的Aclaris的未来依然十分艰难。参考来源：1.https://www.fiercebiotech.com/biotech/aclaris-lays-46-staff-resurrects-zunsemetinib-potential-cancer-treatment2.公司财报本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀ ········

引进/卖出财报临床2期

100 项与 MK2抑制剂(恒瑞医药) 相关的药物交易

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