This is a Phase I/Ib study in which the safety of the combination therapy of RMC-4630 and LY3214996 in the treatment of KRAS mutant cancers will be studied.

开始日期2022-03-31

申办/合作机构

Netherlands Cancer Insitute

[+1]

NL-OMON52379

/ CompletedN/AIIT

Phase I/Ib study with the combination of RMC-4630 and LY3214996 in metastatic KRAS mutant CRC, PDAC and NSCLC - The SHERPA-trial - Phase I/Ib study with the combination of RMC-4630 and LY3214996

开始日期2022-03-31

申办/合作机构-

NCT05054725

/ Completed临床2期

A Phase 2, Open-Label, Multicenter Study of the Combination of RMC-4630 and Sotorasib for Non-Small Cell Lung Cancer Subjects With KRASG12C Mutation After Failure of Prior Standard Therapies

The purpose of this study is to evaluate the antitumor effects of sotorasib and RMC-4630 in subjects with KRASG12C mutant NSCLC

开始日期2021-12-30

申办/合作机构

Revolution Medicines, Inc.

[+2]

100 项与 RMC-4630 相关的临床结果

登录后查看更多信息

100 项与 RMC-4630 相关的转化医学

登录后查看更多信息

100 项与 RMC-4630 相关的专利（医药）

登录后查看更多信息

项与 RMC-4630 相关的文献（医药）

2025-06-01·SLAS Discovery

Combinatorial screen with apoptosis pathway targeted agents alrizomadlin, pelcitoclax, and dasminapant in multi-cell type tumor spheroids

Article

作者: Coussens, Nathan P ; Doroshow, James H ; Silvers, Thomas ; Takebe, Naoko ; Sanchez, Phillip R ; Dexheimer, Thomas S ; Hollingshead, Melinda G ; Teicher, Beverly A ; Chen, Li

Apoptosis, or programmed cell death, plays a critical role in maintaining tissue homeostasis by eliminating damaged or abnormal cells. Dysregulation of apoptosis pathways is a hallmark of cancer, allowing malignant cells to evade cell death and proliferate uncontrollably. Targeting apoptosis pathways has emerged as a promising therapeutic strategy in cancer treatment, aiming to restore the balance between cell survival and death. The MDM2 inhibitor alrizomadlin, the Bcl-2/Bcl-xL inhibitor pelcitoclax, and the IAP family inhibitor dasminapant were evaluated both individually and in combinations with standard of care and investigational anticancer small molecules in a spheroid model of solid tumors. The multi-cell type tumor spheroids were grown from human endothelial cells and mesenchymal stem cells combined with human malignant cells that were either established or patient-derived cell lines from the NCI Patient-Derived Models Repository. The malignant cell lines were derived from a range of solid tumors including uterine carcinosarcoma, synovial sarcoma, rhabdomyosarcoma, soft tissue sarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor (MPNST), pancreas, ovary, colon, breast, and small cell lung cancer. Interactions were observed from combinations of the apoptosis pathway targeted agents. Additionally, interactions were observed from combinations of the apoptosis pathway targeted agents with other agents, including PARP inhibitors, the XPO1 inhibitor eltanexor, and the PI3K inhibitor copanlisib. Enhanced activity was also observed from combinations of the apoptosis pathway targeted agents with MAPK pathway targeted agents, including the MEK inhibitor cobimetinib as well as adagrasib and MRTX1133, which specifically target the KRAS G12C and G12D variants, respectively.

2021-06-24·The New England journal of medicine1区 · 医学

Sotorasib for Lung Cancers with KRAS p.G12C Mutation

1区 · 医学

Article

作者: Ramalingam, Suresh S ; Henary, Haby ; Tran, Qui ; Ngarmchamnanrith, Gataree ; Velcheti, Vamsidhar ; Skoulidis, Ferdinandos ; Borghaei, Hossein ; Kato, Terufumi ; Li, Bob T ; Besse, Benjamin ; Ang, Agnes ; Mather, Omar ; Falchook, Gerald S ; Sacher, Adrian ; Schuler, Martin ; Curioni-Fontecedro, Alessandra ; Price, Timothy J ; Italiano, Antoine ; Takahashi, Toshiaki ; Dy, Grace K ; Anderson, Abraham ; Govindan, Ramaswamy ; Friberg, Gregory ; Barlesi, Fabrice ; Spira, Alexander ; Wolf, Jürgen

BACKGROUND:

Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC).

METHODS:

In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy.

RESULTS:

Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53.

CONCLUSIONS:

In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

128

项与 RMC-4630 相关的新闻（医药）

2025-07-05

·精准药物

Revolution|大环Ras分子胶专利总结

Revolution Medicines成立之初，这家公司的主要研究方向还是抗真菌化合物，与癌症治疗相去甚远。转变发生在2018年。当公司于当年4月完成B轮融资时，让公司开始专注于癌症靶向治疗。科学界长期以来面临一个巨大挑战：RAS基因突变在癌症中广泛存在，但其蛋白质结构特殊，传统方法难以靶向。公司创始人团队决定迎难而上，将火力集中在这一领域。2019年7月，Revolution Medicines完成1亿美元C轮融资，由Boxer Capital领投。此时公司估值已达32.5亿人民币，科学界和投资界都开始关注这家敢于挑战“不可成药”靶点的企业[1]。不同于AMGEN和Mirati等公司选择继续在已有的科学研究基础上，继续创新快速获得了成功，先后上市了托雷塞（sotorasib）和阿达格拉西布（adagrasib）。当然上述的成功离不开先驱者--Shokat、Wells及其同事报告的具有开创性的研究成果ARS-1620。 Martin Burke博士，revolution的灵魂人物，提出了一项雄心勃勃的“化学登月计划”。“如果能够合成自然界中的大多数天然产物分子及其结构类似物，新药研发就再也不用担心没有足够的候选分子了。”Burke博士的愿景大胆而富有革命性。他的实验室开发了一种类似“搭积木”的方法，利用MIDA硼酸盐结构单元进行小分子的迭代组装。这项技术成为Revolution Medicines药物开发的核心平台，使团队能够合成、理解和改进各种具有类似蛋白质功能的复杂天然产物[2]。Burke博士的创新技术平台首创开发出核心候选药物SHP2抑制剂——RMC-4630于2018年6月卖给了赛诺菲。赛诺菲获得RMC-4630的全球独家商业化权利，这一重要合作为Revolution Medicines提供了强大的资金支持和商业渠道，初步证明Revolution Medicines的科研创新能力。除RMC-4630外，Revolution Medicines建立了丰富的研发管线，包括：RAS（ON）抑制剂：针对活性GTP结合形式的RAS大环抑制剂。每次看到revolution的大环KRAS抑制剂还是很有感触的，这么大的分子设计的非常好，兼顾成药性和有效性，并且没有预料中抑制HRAS和NRAS所带来的副作用。我们也写了好几篇RAS抑制剂的进展：突破性新药Zoldonrasib亮相！KRAS G12D肺癌患者迎来治疗曙光。Revolution Medicines来源于上面这句话，他们的mission就是《Revolutionize medicines》，非常艺术的名字源于伟大的使命。从他们的管线可以看到，focus on RAS或者说all in RAS。目前在临床上也已经取得了较多的进展，期待FIC的RAS glue为患者带来临床获益。RMC-6236两项3期临床，NSCLC的2L/3L临床试验RASolve301；另外是PDAC的一项临床以及2个计划3期。今年在AACR上吸引人注意的G12V抑制剂RMC-5127正在临床前研究中，后续还会有RMC-0708(Q61H)和RMC-8839(G13C)正在开发中[1]最近有时间详细看看他们家的产品以及follow的一些数据。1.Elironrasib--RMC-6291-KRAS G12C最早进入到临床研发，临床策略的调整，目前进展显著慢于RMC-6236。临床数据还是不错的，但是副作用也值得警惕。肺癌新药Elironrasib数据更新！联合疗法缓解率100%，但需警惕这些副作用RMC-6291作为最早披露的大环分子，当时惊艳到了非常多的药物设计者，都想知道这么大的分子，是如何设计出来的。至于follow这个还是AMG510，作为最聪明和最诚实的药物设计人，纷纷选择了AMG510。纷纷取得了较好的战绩，国内已经有3家获得了NMPA的批准。最近的JMC也已经披露了RMC-6291的设计来源，首先看下分子胶的机制：RMC-6291优先和cyclophilin A (CypA)结合，然后非共价作用诱导KRASG12C(ON)蛋白结合后形成共价键，最后形成稳定的三元复合物，阻断RAS-RAF的interface。（https://doi.org/10.1021/acs.jmedchem.4c02313）最初的灵感借鉴天然产物（如雷帕霉素、FK506）的免疫亲和蛋白（Immunophilin）作用模式，但选用CypA因其：细胞内丰度高；静电互补性匹配KRAS界面。化合物1是Sanglifehrin A最小药效团，利用Greg Verdine and scientists at Warp Drive Bio合成covalent tethering library获得了化合物1及其化合物蛋白复合物结构，后续通过SBDD陆续设计出化合物2-3等。已经有非常多的公众号介绍详细的SAR过程，在此不再详细赘述。文章非常值得精读，化合物的设计优化策略非常值得药化人员学习。2.Daraxonrasib--RMC-6236-PAN-RAS 有了6291的突破，后续的化合物设计相对明确。最近的JMC也报道了6236的设计以及体外表征。6236也是国内跟随的最多的，也是故事性拉满的化合物，后续我们会提到。关于Revolution Medicinesg公司RMC-6236的临床进展汇总Q&A3.Zoldonrasib--RMC-9805-KRAS G12D目前只有revolution的官网公开的信息，我们之前也看到了临床的药效。临床数据也是非常亮眼，希望国产的跟随可以快速跟进，对国内的G12D突变患者带来获益。突破性新药Zoldonrasib亮相！KRAS G12D肺癌患者迎来治疗曙光4.RMC-5127-KRAS G12V提到这个分子RMC-5127，必须给南京明德点个赞，四元环的IP点不仅好用，还带来了PK的显著提高。revolution真香哈，我也用了。哈哈哈哈哈！革命性突破！KRAS G12V突变癌症迎来“精准克星”，临床前数据惊艳！5.RMC-7977-之前文章公布的一个Lead化合物，后续没见报道。6.罗氏中国-WO2024169914罗氏公布了多个专利，一直在努力，从未轻易放弃，最终本篇专利数据较多，价值较高。实施例24是重点分子，数据最多。结构如下，对比6236主要的IP点在于三并环。有兴趣的可以精读专利。7.阿诺医药-WO2024060966阿诺医药已经公布了多个专利，主要的IP点在于炔的引入，多个化合物在细胞层面展示非常优秀的CTG活性。不知道炔引入后的代谢性质如何。7.南京明德-WO2024067857明德这篇专利被讨论的非常多。单从fast follow来说，非常厉害，快速突破专利，然后化合物的性质还很不错。后续也转给国外的公司，挣到了美元刀乐，真棒！！！上图是专利中的可能6A结构（有药效数据），IP点在于四元桥环，是不是和之前的5127很像，只能说桥环的改变还是很香！！！下面是6A的一些临床前数据，有兴趣的可以看看这个专利，分子不多，主打精准狠，完美符合fast的要求。有一个很少见的数据，全血血浆比例，FDA申请一般会要求，这个竟然在PCC前测了，看来这个化合物在红细胞分布较多。大鼠和犬的PK。也不错可以和6236参照（非同平台数据，全血血浆比值有差异，不能等同）。当然还有非常多的专利，最近已经公开，再次不在一一列举，RAS的分子胶能否上市，需要等revolution的临床结果。希望可以在后续看到积极报道。上述的总结，只是针对已经公开的数据，没有任何倾向性或贬低性，如侵权将删除。参考资料：1.Revolution Medicines：https://www.revmed.com/2.药明在线的雪球专栏：https://xueqiu.com/9650090648/129549825

AACR会议临床3期

2025-04-21

·精准药物

【JMC】中国药科大学钱海团队报道新型SHP2自噬靶向降解剂，对KRAS G12D突变胰腺癌有效

近日，中国药科大学钱海团队在国际权威药物化学期刊《Journal of Medicinal Chemistry》上发表了一篇题为“针对携带KRAS G12D突变的胰腺导管腺癌的新型SHP2自噬靶向降解剂的发现”的研究论文。该研究聚焦于胰腺导管腺癌（PDAC）中携带KRAS G12D突变的肿瘤细胞，通过设计新型的SHP2自噬靶向降解剂（ATTEC），成功实现了对SHP2蛋白的高效降解，并显著抑制了肿瘤的生长和转移。这一成果不仅为靶向SHP2的药物研发提供了新的策略，也为胰腺癌的精准治疗带来了新的策略。一分钟速览研究背景胰腺导管腺癌（PDAC）是一种预后极差的恶性肿瘤，其发病率和死亡率均居高不下。KRAS基因突变是PDAC中最常见的驱动因素之一，尤其是KRAS G12D突变，它导致KRAS蛋白持续激活，进而促进肿瘤的发生和发展。然而，针对KRAS G12D突变的直接抑制剂研发面临诸多挑战。SHP2是一种重要的信号转导蛋白，它在KRAS驱动的肿瘤中发挥关键作用，通过调节KRAS的活性来促进肿瘤进展。因此，靶向SHP2成为一种潜在的治疗策略。重点内容在这项研究中，钱海团队基于自噬-溶酶体途径（ALP）设计了一系列新型的SHP2 ATTEC降解剂。这些降解剂通过招募自噬相关蛋白LC3，促进SHP2与LC3的结合，进而诱导SHP2的溶酶体降解。研究发现，其中一种优化的降解剂11n能够显著增强SHP2与LC3之间的相互作用，并在体外和体内实验中展现出对KRAS G12D突变癌细胞的高效抑制作用。11n不仅能够诱导肿瘤细胞凋亡，还能显著抑制肿瘤细胞的侵袭和转移能力，其抗肿瘤效果在小鼠模型中得到了进一步验证。研究总结该研究的创新之处在于利用自噬机制来降解SHP2蛋白，为胰腺癌的治疗提供了一种全新的思路。通过靶向SHP2这一关键信号分子，研究团队成功开发出了一种具有高效降解能力和抗肿瘤活性的新型降解剂。这一成果不仅丰富了自噬靶向降解剂的研究领域，也为未来胰腺癌的精准治疗提供了有力的候选药物。图片来源：ACS详细阅读01Background研究背景胰腺导管腺癌（PDAC）是一种起源于胰腺的致命恶性肿瘤，占所有胰腺癌的约90%，其发病率在过去几十年中不断增加。PDAC早期症状隐匿，约80%的患者在确诊时已处于晚期，且胰腺组织的复杂位置使得手术干预效果有限。目前，吉西他滨为基础的联合疗法仍是主要治疗选择，但分子靶向药物如厄洛替尼、奥拉帕尼和拉罗替尼等相较于化疗并无显著优势。KRAS基因突变是PDAC中最常见的驱动因素，尤其是KRAS G12D亚型，其突变导致KRAS蛋白无法从GTP活性形式转变为GDP非活性形式，从而持续激活并促进肿瘤发生。尽管Mirati Therapeutics开发的KRAS G12D选择性抑制剂MRTX1133显示出潜力，但其存在内在和获得性耐药、单药疗效有限和口服生物利用度低等问题，因此迫切需要开发针对KRAS G12D突变PDAC的安全有效的新疗法。SHP2是一种由PTPN11基因编码的蛋白酪氨酸磷酸酶，其在KRAS驱动的癌症中作为鸟苷酸交换因子（GEF）介导KRAS-GDP与KRAS-GTP之间的转换，并增强GRB2-SOS1与KRAS的结合以激活KRAS。此外，SHP2还被证明可以延缓肿瘤进展并提高癌症免疫治疗的疗效。然而，由于SHP2的药理学抑制存在诸多挑战，目前尚未有高效且特异性的SHP2抑制剂。近年来，靶向蛋白质降解（TPD）技术为创新药物研发开辟了新途径，其中蛋白降解靶向嵌合体（PROTACs）是主要的TPD技术。与之相比，自噬-溶酶体途径（ALP）是另一种细胞降解机制，主要负责清除大分子蛋白、蛋白聚集体、细胞器和细胞外蛋白。2019年，Lu团队首次提出了基于自噬体标记物LC3的自噬体靶向化合物（ATTEC）策略。本研究中，作者基于SHP-099（一种SHP2的变构抑制剂）和LC3配体AN2，设计了一系列新型的SHP2 ATTEC降解剂，旨在通过自噬机制实现SHP2的降解，为KRAS G12D突变PDAC提供新的治疗策略。图片来源：ACS02Drug Design药物设计与评价①药物设计作者首先基于TCGA和GTEx数据库分析了胰腺腺癌与非匹配正常组织之间SHP2和LC3B基因表达的显著差异，并通过Western blotting验证了SHP2和LC3B在PANC-1和AsPC-1癌细胞中的高表达，表明利用自噬途径实现SHP2的高效降解是合理的策略。随后，作者设计了一系列基于自噬的SHP2靶向自噬体靶向化合物（ATTECs），这些化合物包含SHP2配体、柔性连接链和LC3配体，旨在通过招募SHP2和LC3来触发自噬体融合和溶酶体介导的降解。为了探索AN2结构修饰的合理性及其被自噬体吞噬的能力，作者合成了一个带有FITC荧光探针的LC3识别探针（AN2-FITC），并通过细胞热位移分析（CETSA）和共聚焦显微镜成像验证了其与LC3B的结合能力和进入自噬体的能力。基于SHP-099（一种SHP2变构抑制剂）的结构，作者进一步设计并合成了一系列SHP2靶向ATTEC降解剂，并通过细胞实验评估了这些降解剂对SHP2蛋白降解的效率，发现随着连接链长度的增加，降解效率逐渐提高，其中某些化合物展现出较好的降解活性。图片来源：ACS②降解活性构效探究作者详细评估了一系列新型SHP2靶向自噬体靶向化合物（ATTEC）降解剂的降解效率和抗增殖活性。研究发现，这些降解剂在PANC-1细胞（携带KRAS G12D突变）中能够有效触发SHP2蛋白的降解，且随着连接链长度的增加，降解效率逐渐提高。特别是当连接链长度为五到七个碳原子时，降解效率显著提升，其中化合物11h在10.0 μM浓度下展现出最高的降解率（70.59%）。此外，基于聚乙二醇（PEG）连接链的降解剂（如11k和11l）也表现出良好的降解潜力，其降解效率是四碳连接链化合物11e的两倍以上。为了进一步优化降解剂的结构，作者还对SHP2抑制剂的二氯苯基部分进行了替换，发现含有苯并呋喃基、噻吩基和三氟甲基苯基的降解剂（如11n和11o）具有与11l相当的降解效率，显示出良好的降解活性和选择性。在抗增殖活性方面，这些高效降解SHP2的化合物在体外对多种胰腺导管腺癌（PDAC）细胞系（包括携带KRAS G12D突变的PANC-1和AsPC-1细胞，以及野生型KRAS的BxPC-3和4T1细胞）表现出显著的抑制效果。特别是化合物11h、11k、11l、11n和11o在PANC-1和AsPC-1细胞中的抑制活性显著优于SHP2抑制剂SHP-099，其半数抑制浓度（IC50）值远低于SHP-099。此外，这些降解剂对正常细胞HEK-293T的毒性较低，表明其具有较好的选择性。综合来看，这些结果表明，基于自噬机制的SHP2降解剂在抑制KRAS G12D突变的PDAC细胞增殖方面具有显著的潜力，且通过合理设计连接链和替换基团可以进一步优化其降解效率和抗肿瘤活性。图片来源：ACS03In vitro In Vivo体内外评价①化合物11n与SHP2和自噬相关蛋白LC3之间的相互作用及其诱导SHP2有效降解的机制研究发现，11n能够以剂量依赖的方式显著降低胰腺腺癌细胞中SHP2蛋白的水平，其在PANC-1和AsPC-1细胞中的半数降解浓度（DC50）分别为0.14 μM和0.10 μM。通过预处理自噬抑制剂（如Bafilomycin A1、Chloroquine和NH4Cl），可以成功逆转11n诱导的SHP2降解，表明11n诱导的SHP2降解依赖于自噬和SHP2蛋白本身。此外，CETSA实验显示，11n能够显著稳定SHP2蛋白，使其在较高温度下不易变性，表明11n与SHP2具有较强的结合能力。Co-IP实验进一步证实了11n能够促进SHP2与LC3之间形成三元复合物。通过分子对接模拟，作者发现11n能够与SHP2的关键活性口袋结合，其氨基与SHP2的Glu 250形成氢键，而其末端的自噬基序则有助于与LC3蛋白的识别。定量蛋白质组学分析也表明，11n处理后SHP2蛋白水平显著下降，进一步验证了11n通过促进SHP2与LC3的相互作用，有效诱导了SHP2的自噬降解。图片来源：ACS②化合物11n对KRAS G12D突变胰腺导管腺癌（PDAC）细胞中KRAS活性状态的影响研究发现，11n能够选择性地降低KRAS G12D突变细胞中磷酸化ErK1/2的表达水平，而对野生型KRAS细胞中的磷酸化ErK1/2没有显著影响。磷酸化ErK1/2是KRAS下游信号通路的关键蛋白，其活性与KRAS的活性状态密切相关。此外，11n还显著降低了c-Myc的表达，c-Myc是一种与KRAS信号通路相关的转录因子，其在PDAC中通常高表达并与肿瘤的增殖和存活相关。这些结果表明，11n通过抑制KRAS信号通路的活性，选择性地将KRAS G12D突变的PDAC细胞推向失活状态，从而发挥其抗肿瘤作用。这一发现进一步证实了11n作为一种潜在的靶向治疗药物，能够特异性地影响KRAS G12D突变细胞的信号传导，为胰腺癌的精准治疗提供了新的策略。图片来源：ACS③化合物11n对PANC-1和AsPC-1细胞凋亡的影响实验结果显示，11n能够显著促进这两种细胞进入早期和晚期凋亡阶段，并且这种效果是剂量依赖的。在1.0 μM的浓度下，经过24小时处理后，PANC-1和AsPC-1细胞的总凋亡率分别达到了29.5%和31.3%。此外，Hoechst 33258染色实验观察到，11n处理后的细胞核呈现出明显的浓缩和染色增强现象，这进一步证实了细胞凋亡的发生。为了深入了解11n诱导凋亡的分子机制，作者通过Western blot实验检测了凋亡相关蛋白的表达变化。结果表明，11n显著上调了促凋亡蛋白cleaved caspase-3和Bax的表达，同时下调了抗凋亡蛋白Bcl-2和caspase-3的表达水平。这些变化表明11n能够激活细胞内的凋亡信号通路，从而有效地诱导PANC-1和AsPC-1细胞的凋亡。这一发现不仅揭示了11n的细胞毒性作用机制，还为其作为潜在的抗肿瘤药物提供了重要的实验依据。图片来源：ACS④化合物11n对PANC-1和AsPC-1细胞侵袭和转移能力的影响实验结果表明，11n能够显著抑制这两种细胞的侵袭能力，并且这种抑制作用是浓度依赖的。通过Transwell实验，作者观察到11n处理后的细胞侵袭能力明显降低。此外，在分子水平上，11n能够显著上调E-钙黏蛋白（E-cadherin）的表达，同时显著下调N-钙黏蛋白（N-cadherin）和波形蛋白（vimentin）的表达。这些蛋白是上皮-间质转化（EMT）的关键标志物，其表达变化与肿瘤细胞的侵袭和转移能力密切相关。免疫荧光实验进一步验证了11n处理后细胞中vimentin表达的下调。这些结果表明，11n通过调节EMT相关蛋白的表达，显著抑制了PANC-1和AsPC-1细胞的侵袭和转移能力，从而在体外实验中展现出良好的抗肿瘤转移潜力。图片来源：ACS⑤化合物11n在体内模型中对肿瘤生长的抑制作用研究中使用了PANC-1细胞建立的皮下异种移植瘤模型，通过给药实验评估了11n的抗肿瘤效果。实验结果显示，11n能够显著抑制肿瘤的生长，且这种抑制作用具有剂量依赖性。具体来说，11n以15 mg/kg和30 mg/kg的剂量给药时，肿瘤体积显著减小，其中30 mg/kg剂量组的肿瘤抑制率达到了75.16%。此外，11n在体内表现出良好的药代动力学特性，具有较长的半衰期（T1/2 = 1.19小时）和较高的血浆暴露量（AUC = 4158.65 ng·h/mL），能够有效维持药物浓度，从而发挥抗肿瘤作用。在实验过程中，11n的给药并未引起小鼠体重的显著变化，表明其具有较好的耐受性。组织学检查显示，11n处理的小鼠主要器官（如心、肝、脾、肺和肾）未出现明显的病理损伤，进一步证实了其在体内的安全性。此外，免疫组化分析显示，11n能够显著降低肿瘤组织中Ki-67和SHP2的表达水平，同时减少肿瘤细胞的侵袭能力。这些结果表明，化合物11n在体内模型中不仅能够有效抑制肿瘤生长，还具有良好的安全性和耐受性，为后续的药物开发和临床应用提供了有力的实验支持。图片来源：ACS总结KRAS G12D突变是胰腺导管腺癌（PDAC）的关键驱动因素之一，而SHP2作为一种重要的信号转导蛋白，被认为是治疗KRAS G12D突变PDAC的潜在靶点。然而，开发高效且特异性的SHP2抑制剂一直面临挑战。本研究基于自噬体靶向化合物（ATTEC）策略，设计并合成了一系列新型的SHP2降解剂。其中，化合物11n表现出显著的SHP2降解能力和抗肿瘤活性。研究结果表明，11n能够通过增强SHP2与自噬相关蛋白LC3之间的相互作用，有效诱导SHP2的溶酶体降解。在体外实验中，11n显著抑制了KRAS G12D突变癌细胞的增殖、侵袭和转移能力，并诱导细胞凋亡。在体内实验中，11n显著抑制了PDAC肿瘤的生长，且未引起明显的毒副作用。这些发现不仅证明了基于自噬机制的SHP2降解剂在治疗KRAS G12D突变PDAC中的潜力，还为开发新型抗肿瘤药物提供了重要的理论和实验依据。参考来源：https://doi.org/10.1021/acs.jmedchem.4c02682声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床终止

2025-03-06

·PRNewswire

TEPMETKO Continues to Strengthens its Position as a Leading METex14 Skipping NSCLC Therapy | DelveInsight

With increasing biomarker-driven cancer treatments, TEPMETKO benefits from growing adoption in precision oncology. Competition from other MET inhibitors like TABRECTA (capmatinib) exists, but TEPMETKO's once-daily dosing and efficacy profile offer differentiation. LAS VEGAS, March 6, 2025 /PRNewswire/ -- DelveInsight's " TEPMETKO Market Size, Forecast, and Market Insight Report" highlights the details around TEPMETKO, a kinase inhibitor indicated for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. The report provides product descriptions, patent details, and competitor products (marketed and emerging therapies) of TEPMETKO. The report also highlights the historical and forecasted sales from 2020 to 2034 segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. EMD Serono's TEPMETKO (tepotinib) Overview TEPMETKO is a kinase inhibitor prescribed for adult patients with metastatic non-small cell lung cancer (NSCLC) carrying MET exon 14 skipping alterations. The active component is Tepotinib (as hydrochloride monohydrate), administered orally. Patients should be cautioned about the heightened risk of severe or fatal interstitial lung disease/pneumonitis, liver toxicity, and potential embryo-fetal toxicity, necessitating effective contraception during and shortly after treatment. Tepotinib specifically targets MET, including variants with exon 14 skipping mutations. It blocks HGF-dependent and independent MET phosphorylation, disrupting MET-driven signaling pathways. Additionally, at clinically relevant concentrations, Tepotinib inhibits melatonin 2 and imidazoline 1 receptors. In vitro studies show that it suppresses tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent cancer cells. In mouse models with MET-driven tumors, including those with MET exon 14 skipping alterations, Tepotinib reduced tumor growth, sustained MET phosphorylation inhibition, and, in one case, decreased metastasis formation. The recommended dose of TEPMETKO is 450 mg taken orally once daily until disease progression or intolerable toxicity occurs. Patients should take it at the same time each day, swallowing tablets whole without chewing, crushing, or splitting them. If a dose is missed and less than eight hours remain until the next scheduled dose, patients should skip it. In cases of vomiting after taking TEPMETKO, the next dose should be taken at the usual time. Learn more about TEPMETKO projected market size for NSCLC @ TEPMETKO Market Potential Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 81% of all diagnosed cases. Early detection greatly improves outcomes, but diagnosing NSCLC and other lung cancers is challenging because their symptoms are often mistaken for common illnesses or the long-term effects of smoking. Consequently, 80% of NSCLC cases are already at advanced stages by the time they are identified, making treatment more difficult. Around 80% of EGFR mutations in NSCLC involve either exon 19 deletions or the exon 21 L858R substitution, both of which are classified as sensitizing mutations. Until the last decade, chemotherapy was the primary treatment for advanced and metastatic lung cancer. However, this changed in 2015 with the approval of the first immune checkpoint inhibitor (ICI), KEYTRUDA (pembrolizumab), as a second-line therapy for advanced cases. This was followed by TECENTRIQ (atezolizumab) in 2016. Both therapies were later approved for first-line treatment, broadening their use to a larger patient population. In 2020, the combination of OPDIVO (nivolumab) and ipilimumab also received approval as a first-line treatment for metastatic NSCLC. According to DelveInsight, the NSCLC market size across the 7MM is projected to grow from USD 30 billion in 2024, with a substantial CAGR through 2034. This growth is largely driven by the introduction of emerging therapies during the forecast period (2025–2034). Discover more about the NSCLC market in detail @ Non-small Cell Lung Cancer Market Report Emerging Competitors of TEPMETKO The NSCLC pipeline is very robust with the promising therapies such as Telisotuzumab vedotin (AbbVie), Patritumab deruxtecan (Daiichi Sankyo/AstraZeneca), Datopotamab deruxtecan (Daiichi Sankyo/AstraZeneca), Eftilagimod alpha (Immutep), BNT311/GEN1046 (acasunlimab) (Genmab), V940 (mRNA-4157) + Pembrolizumab (Moderna Therapeutics/Merck), Plinabulin + Docetaxel (BeyondSpring), Olomorasib (LY3537982) (Eli Lilly and Company), Zipalertinib (Cullinan Oncology/Taiho Pharma), Ceralasertib (AZD6738) (AstraZeneca), TEDOPI (EP-2101; IDM 2101; OSE-2101) (OSE Immuno-therapeutics), Sigvotatug vedotin (PF08046047) (Pfizer), ANKTIVA (N-803) (ImmunityBio), Aumolertinib/Almonertinib/HS-10206 (Jiangsu Hansoh Pharmaceutical), Niraparib (GSK), Savolitinib (AstraZeneca/Hutchison MediPharma), TRODELVY (Gilead Sciences), Pyrotinib (Jiangsu HengRui Medicine), Ociperlimab (BGB-A1217) (BieGene), Volrustomig (AstraZeneca), Gotistobart (BNT316/ONC-392) (OncoC4/BioNTech), Ivonescimab (AK112/SMT112) (Akeso Biopharma/Summit Therapeutics), ZYNYZ (retifanlimab/INCMGA00012) (Incyte/Macrogenics), Divarasib (GDC-6036) (Roche/Genentech), Tiragolumab (RG6058) (Roche), Sacituzumab Tirumotecan (Merck and Kelun-Biotech), JEMPERLI (dostarlimab/TSR-042) (GSK and AnaptysBio), Zongertinib (BI-1810631) (Boehringer Ingelheim), BAY 2927088 (Bayer), Serplulimab (HLX10) (Shanghai Henlius Biotech), Rilvegostomig (AZD2936) (AstraZeneca), MK-1084 (Merck, Taiho Pharmaceutical, and Astex), Domvanalimab (Arcus Biosciences and Gilead Sciences), OPDUALAG (nivolumab and relatlimab) (Bristol-Myers Squibb), Belrestotug + JEMPERLI (iTeos Therapeutics and GSK), Firmonertinib (ArriVent BioPharma), Sunvozertinib (DZD9008) (Dizal Pharmaceutical), Cobolimab (GSK), Livmoniplimab (AbbVie), Fianlimab (REGN3767) (Regeneron Pharmaceuticals), BNT327/PM8002 (Biotheus/BioNTech), HS-20117 (Hansoh BioMedical), IO102-IO103 + Pembrolizumab (IO Biotech), Naptumomab estafenatox (NeoTX Therapeutics/Active Biotech), FF-10832 (FUJIFILM Corporation), BNT116 (BioNTechSE/Regeneron Pharmaceuticals), CAN-2409 (Candel Therapeutics), Mecbotamab Vedotin (BA3011/CAB-AXL-ADC) (BioAtla), Bemcentinib (BGB 324/BGB-3234/R-428) (BerGenBio/Rigel Pharmaceuticals), DOVBLERON (taletrectinib/AB-106/IBI-344) (Nuvation Bio/Innovent Biologics/Daiichi Sankyo/Nippon Kayaku), Lifileucel (Iovance Biotherapeutics), IBI363 (Innovent Biologics), Sotevtamab (AB-16B5) (Alethia Biotherapeutics), Avutometinib (VS6766) (Verastem Oncology), Vebreltinib (APL-101) (Apollomics), LP-300 (Lantern Pharma), JNJ-90301900 (Johnson & Johnson Innovative Medicine), AMG 193 (Amgen), Luveltamab tazevibulin (Sutro Biopharma), PRT3789 (Prelude Therapeutics), Disitamab vedotin (Seagen), PADCEV (enfortumab vedotin) (Astellas Pharma), RP1 (Replimune), TIVDAK (tisotumab vedotin) (Seagen), Zanidatamab (Jazz Pharmaceuticals), Utidelone injectable (UTD1) (Beijing Biostar Pharmaceuticals), REGN5093-M114 (Regeneron Pharmaceuticals), SLC-391 (SignalChem Lifesciences), fulzerasib (GenFleet), Davutamig (REGN5093) (Regeneron Pharmaceuticals), TAS3351 (Taiho Oncology), H002 (RedCloud Bio), JIN-A02 (J INTS BIO), FWD1509 (Forward Pharma), Sabestomig (AZD7789) (AstraZeneca), Sasanlimab (Pfizer), Selvigaltin (GB1211) (Galecto Biotech), Vepafestinib Helsinn (Healthcare/Taiho Pharmaceutical), EP0031 (A400/ KL590586) (Ellipses Pharma/Kelun-Biotech), Pamvatamig (MCLA-129) (Merus), Zidesamtinib (NVL-520) (Nuvalent), NVL-655 (Nuvalent), RMC-4630 (Revolution Medicines), REQORSA (quaratusugene ozeplasmid) (Genprex), PDC*lung01 (PDC*line Pharma), Evalstotug (BA3071) (BioAtla and BeiGene), PT-112 (Promontory Therapeutics), MRT-2359 (Monte Rosa Therapeutics), GAIA-102 (GAIA BioMedicine), Rigosertib (Traws Pharma), HMBD-001 (Hummingbird Bioscience), PLB1004 (Avistone Biotechnology), ANS03 (Avistone Biotechnology), MYTX-011 (Mythic Therapeutics), A166 (Sichuan Kelun-Biotech Bio-pharmaceutical), Atamparib (BN-2397) (Ribon Therapeutics), DELTACEL (KB-GDT-01) (Kiromic BioPharma), Carotuximab (ENV-105) (Kairos Pharma), YL202 (MediLink Therapeutics), and others. To know more about the number of competing drugs in development, visit @ TEPMETKO Market Positioning Compared to Other Drugs Key Milestones of TEPMETKO In February 2024, the FDA granted traditional approval to TEPMETKO for adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. In February 2022, the EC approved TEPMETKO as monotherapy for the treatment of adult patients with advanced NSCLC harboring alterations leading to METex14 skipping who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy. In February 2021, Merck announced that the US FDA has approved TEPMETKO following priority review for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. This indication was approved under accelerated approval based on ORR and DOR. In October 2020, TEPMETKO received ODD for treating NSCLC with MET genomic tumor aberrations In March 2020, EMD Serono (the biopharmaceutical business of Merck KGaA), announced that the MHLW approved TEPMETKO for the treatment of patients with unresectable, advanced, or recurrent NSCLC with METex14 skipping alterations. In September 2019, the US FDA granted BTD for tepotinib in patients with metastatic NSCLC harboring METex14 skipping alterations who progressed following platinum-based cancer therapy Discover how TEPMETKO is shaping the NSCLC treatment landscape @ TEPMETKO NSCLC TEPMETKO Market Dynamics TEPMETKO competes in a growing but highly specialized market where MET-targeted therapies are gaining traction due to their efficacy in addressing MET-altered tumors. The market for MET inhibitors is expanding as precision oncology advances and molecular diagnostics become more widely available, enabling better identification of patients who would benefit from targeted treatments like TEPMETKO. A key factor shaping TEPMETKO's market dynamics is competition. It directly competes with Novartis' TABRECTA (capmatinib), another MET inhibitor approved for the same indication. While TEPMETKO offers the advantage of once-daily dosing compared to TABRECTA's twice-daily regimen, both drugs have similar efficacy profiles, making physician and patient preference an important differentiator. Additionally, broader competition from next-generation MET inhibitors and combination therapies in clinical trials could impact TEPMETKO's long-term market position. Regulatory approvals and market access play a crucial role in TEPMETKO's adoption. The drug has been approved in multiple regions, including the U.S., Europe, and Japan, but reimbursement and pricing strategies vary by market. Payer policies, along with the cost-benefit analysis of MET inhibitors compared to other targeted therapies, influence prescription trends. Furthermore, real-world evidence and post-marketing studies will be critical in demonstrating TEPMETKO's sustained effectiveness and safety, which could support expanded indications and increased market penetration. Looking ahead, the MET inhibitor market is expected to grow with advances in biomarker-driven therapy, further refining patient selection. TEPMETKO's success will depend on continued clinical development, potential label expansions, and strategic partnerships to strengthen its competitive edge. As new entrants emerge, Merck KGaA's ability to differentiate TEPMETKO through combination strategies or enhanced formulations may determine its long-term sustainability in this evolving landscape. Dive deeper to get more insight into TEPMETKO's strengths & weaknesses relative to competitors @ TEPMETKO Market Drug Report Table of Contents Related Reports Non-small Cell Lung Cancer Market Non-small Cell Lung Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key NSCLC companies including Daiichi Sankyo, AstraZeneca, Gilead Sciences, BieGene, AbbVie, Roche, Merck, Novartis, Pfizer, Takeda Pharmaceuticals, Eli Lilly, BerGenBio, GlaxoSmithKline, Duality biologics, among others. Non-small Cell Lung Cancer Pipeline Non-small Cell Lung Cancer Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key non-small cell lung cancer companies, including BridgeBio Pharma, Daiichi Sankyo, EMD Serono, Merck, BridgeBio Pharma, Abbvie, Pfizer, Eli Lilly and Company BioNTech SE, Shenzhen TargetRx, Taiho Pharmaceutical, Chong Kun Dang, Bristol Myers Squibb, Innovent Biologics, Xuanzhu Biopharmaceutical, Bayer, GeneScience Pharmaceuticals, InventisBio, Apollomics, Imugene, Ono Pharmaceutical, Pierre Fabre, Jiangsu Hengrui Medicine Co., Bristol-Myers Squibb, Surface Oncology, Inhibrx, Sinocelltech, Mirati Therapeutics, REVOLUTION Medicines, Yong Shun Technology Development, Iovance Biotherapeutics, Galecto Biotech, among others. C-MET Metastatic Non-small Cell Lung Cancer Market C-MET Metastatic Non-small Cell Lung Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key C-MET mNSCLC companies, including Novartis, Merck, EMD Serono, AbbVie, Regeneron Pharmaceuticals, Mythic Therapeutics, Apollomics, Johnson & Johnson Innovation, Haihe Biopharma, among others. C-MET Non-small Cell Lung Cancer Pipeline C-MET Non-small Cell Lung Cancer Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key C-MET non-small cell lung cancer companies, including AbbVie, Janssen Research & Development, Beijing Pearl Biotechnology Limited Liability Company, Novartis, 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

上市批准免疫疗法优先审批

100 项与 RMC-4630 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
非小细胞肺癌	临床2期	美国	Revolution Medicines, Inc.	2021-12-30
非小细胞肺癌	临床2期	澳大利亚	Revolution Medicines, Inc.	2021-12-30
非小细胞肺癌	临床2期	加拿大	Revolution Medicines, Inc.	2021-12-30
非小细胞肺癌	临床2期	法国	Revolution Medicines, Inc.	2021-12-30
非小细胞肺癌	临床2期	德国	Revolution Medicines, Inc.	2021-12-30
非小细胞肺癌	临床2期	意大利	Revolution Medicines, Inc.	2021-12-30
非小细胞肺癌	临床2期	西班牙	Revolution Medicines, Inc.	2021-12-30
非小细胞肺癌	临床2期	中国台湾	Revolution Medicines, Inc.	2021-12-30
非小细胞肺癌	临床2期	英国	Revolution Medicines, Inc.	2021-12-30
肿瘤转移	临床2期	美国	Revolution Medicines, Inc.	2020-06-09

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


AACR2025	N/A	胰腺癌	-	RMC4630	醖鏇淵願顧鑰鏇鹹廠鬱(窪壓構衊廠鏇襯獵製鏇) = 淵壓築遞願觸壓廠簾鏇遞膚壓衊遞膚製艱醖鹹 (鑰願夢網膚襯積鏇簾艱 ) 更多	-	2025-04-28
				Nab-paclitaxel and gemcitabine (NPT-GEM)	醖鏇淵願顧鑰鏇鹹廠鬱(窪壓構衊廠鏇襯獵製鏇) = 廠窪構鑰遞淵淵憲鏇鹽遞膚壓衊遞膚製艱醖鹹 (鑰願夢網膚襯積鏇簾艱 ) 更多
NCT04418661 (CTgov)	临床1/2期	肿瘤转移	65	Pembrolizumab+Vociprotafib (Part 1- SAR442720 200mg BIW + Pembrolizumab)	製壓襯鏇構鏇壓糧廠膚 = 顧淵壓糧網積網構壓簾鏇襯積窪齋築顧淵鏇廠 (膚願夢蓋窪繭鑰鑰淵齋, 鹹鬱獵壓艱鬱醖鬱窪繭 ~ 蓋積壓獵製憲艱構衊繭) 更多	-	2025-04-20
				Adagrasib+Vociprotafib (Part 3A- SAR442720 100mg BIW + Adagrasib)	築網繭窪鬱壓願簾艱鹹 = 襯鏇憲觸構鏇餘繭醖廠醖鹽顧餘構構獵鹽壓鹹 (積構鹽觸蓋壓選淵廠醖, 獵鏇憲壓蓋願觸鬱艱製 ~ 壓蓋夢鬱積膚積構淵鹽) 更多
NCT03989115 (CTgov)	临床1/2期	实体瘤 \| 晚期恶性实体瘤	113	Cobimetinib+RMC-4630 (Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7))	夢鹹醖齋齋襯醖鏇積艱 = 齋淵獵繭膚鏇顧鏇製憲鑰窪獵廠構窪範構鹽積 (願簾築廠齋窪觸製範淵, 艱憲艱醖廠廠製製衊淵 ~ 網襯憲膚壓願醖襯鏇簾) 更多	-	2023-06-26
				Cobimetinib+RMC-4630 (Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7))	夢鹹醖齋齋襯醖鏇積艱 = 網鏇糧餘艱顧餘願蓋醖鑰窪獵廠構窪範構鹽積 (願簾築廠齋窪觸製範淵, 遞鬱簾顧醖蓋窪觸網淵 ~ 廠築憲齋醖鹽積糧憲蓋) 更多
NCT03634982 (AACR 12021 \| AACR 22021) 人工标引	临床1期	实体瘤 KRAS Mutation	104	overall	選積積廠鏇遞製衊鹹選(遞簾鏇構觸鏇觸廠廠簾) = 200 mg D1D2, delivering a 400 mg weekly dose intensity 襯願積構衊簾獵蓋鏇餘 (憲鑰顧糧製蓋顧鏇獵鑰 ) 更多	积极	2021-04-10
				RMC-4630 (KRAS MUT NSCLC)