Simurosertib

关注小药说药，一起成长！ 前言 合成致死性是一种遗传现象，即单个基因缺陷与细胞存活相容，但两个基因的同时缺陷导致细胞死亡或细胞适应性受损。合成致死性提供了一个独特的机会，可以间接靶向以前被认为“难以成药”的蛋白质，包括携带功能丧失（LOF）突变的关键肿瘤抑制蛋白和由扩增或其他基因组改变引起的过表达致癌蛋白。这些与环境相关的相互作用是癌细胞固有和特异性的，因此提供了选择性靶向这些细胞的机会，同时保留了缺乏相关基因组背景的非癌细胞。 目前，PARP抑制剂已经在BRCA突变癌症患者中获得临床成功。在此推动下，针对DNA损伤反应途径中多种合成致死相互作用的新型药物正在临床开发中，针对跨越表观遗传、代谢和增殖途径改变的合成致死相互作用的合理策略也已出现，并进入临床前和早期临床试验阶段。 靶向合成致死相互作用 DNA损伤反应（DDR）网络可以保持基因组稳定性，抑制复制应激，保护受损的复制叉，并确保高保真DNA复制。DDR成分的遗传性和获得性细胞缺陷与基因组不稳定性的积累有关，导致肿瘤发生和癌症进展。同时，具有这些缺陷的细胞变得依赖于补偿DDR途径生存，从而为合成致命靶向创造了机会。 DNA损伤信号：靶向ATR、ATM和DNA-PK ATR、ATM和CHK1激酶的抑制剂主要通过抑制必需的细胞周期检查点来利用细胞复制应激，导致过早进入有丝分裂和细胞死亡。ATR是一种丝氨酸/苏氨酸蛋白激酶，属于磷脂酰肌醇3-激酶相关激酶（PIKK）家族。当DNA发生损伤时，ATR被激活，并通过下游信号通路参与DNA损伤的检测、复制叉的稳定和损伤修复；激酶ATM通过调节DDR内下游激酶的活性和控制细胞周期检查点进程，在DNA双链断裂（DSB）的修复中起着关键作用；DNA-PK是另一种磷脂酰肌醇3-激酶相关激酶（PIKK），在DNA损伤部位充当邻近修复蛋白的蛋白质支架，在非同源末端连接（NHEJ）中起着关键作用。许多肿瘤细胞由于DNA修复通路的缺陷，高度依赖这些激酶途径来维持其生存和增殖。因此，ATR、ATM和DNA-PK抑制剂与这些缺陷相结合，可导致肿瘤细胞发生合成致死。 多种ATR抑制剂已处于临床开发中，包括berzosertib、ceralasterib、elimusertib、camonsertib、tuvusertib、ART0380、ATRN-119、ATG-018和IMP9064等；正在临床试验中测试的ATM抑制剂包括AZD1390和双重ATM和DNA-PK抑制剂XRD-0394和M4076，临床开发中的DNA-PK抑制剂包括AZD7648和peposertib。 DNA复制和细胞分裂：WEE1、PKMYT1、CDC7和PLK4 Wee样激酶1（WEE1）通过催化CDK1和CDK2在Tyr15位置的抑制性磷酸化来调节细胞周期通过G2/M和S检查点的进程。WEE1的抑制在G1/S失调的情况下是合成致死的，例如由CCNE1扩增或TP53突变引起的G1/S失调。正在临床试验中测试的WEE1抑制剂包括adavosertib、azenosertib、Debio 0123、IMP7068、SY-4835、SC0191和ATRN-W1051。 蛋白激酶，膜相关酪氨酸-苏氨酸1（PKMYT1）是一种细胞膜相关丝氨酸-苏氨酸蛋白激酶，也调节CDK1和G2/M检查点。功能基因组筛选的数据表明，PKMYT1失活与CCNE1扩增具有合成致死性。此外，除了CCNE1扩增，编码E3泛素连接酶FBXW7基因中的LOF突变和编码PP2A磷酸酶亚基PPP2R1A的基因也可通过PKMYT1抑制靶向。 细胞分裂周期7（CDC7）激酶在触发复制起点激活中起着重要作用。携带功能获得TP53突变的细胞依赖于CDC7依赖性DNA复制，这是由于与致癌转录因子MYB合作促进癌症细胞中的CDC7激活。在携带TP53突变的癌症细胞中，CDC7的药理学抑制诱导选择性衰老，而mTOR信号与CDC7联合抑制在促进凋亡细胞死亡方面非常有效。然而，尽管具有明显的临床前活性，但几种CDC7抑制剂（BMS-863233、TAK-931、NMS-1116354和LY3143921）在早期试验中未能显示出足够的疗效。 Polo 样激酶4（PLK4）是一种调节中心粒生物发生的激酶，中心粒是有丝分裂纺锤体组装和染色体分离所需的中心体的重要组成部分。中心粒周围的蛋白质是另一个关键的中心体成分，受E3泛素连接酶TRIM37的负调控。TRIM37的扩增（通常在神经母细胞瘤和乳腺癌中观察到）导致中心体物质耗竭，从而增加了对中心粒进行有丝分裂纺锤体组装的依赖，并使PLK4抑制在这种情况下成为一种有吸引力的治疗策略。目前，两种PLK4抑制剂CFI-400945和RP-1664正在临床试验中进行测试。 DNA修复：WRN、POLQ和USP1 POLQ和泛素特异性蛋白酶1（USP1）是携带BRCA1/2缺陷的癌症中临床相关的合成致死靶点。POLQ是一种广泛保守的DNA聚合酶，也是DSB修复过程中易出错的MMEJ途径的核心介体。来自几项试验的数据表明，POLQ抑制和BRCA1/2缺乏之间存在合成致死关系，这归因于癌症HRR缺陷（HRD）细胞对MMEJ DNA修复的高度依赖性。测试各种POLQ抑制剂的早期试验正在进行中，包括ART4215、novobiocin、ART6043和GSK4524101，作为单一疗法或与各种PARP抑制剂联合使用。 USP1是一种去泛素酶，调节关键的范可尼贫血复合物和跨损伤合成底物，同时抑制NHEJ。在BRCA1缺陷细胞中，USP1在复制叉处特别活跃，其与叉DNA结合并被其激活，同时介导叉保护；抑制USP1会导致复制叉失稳、叉保护失败和细胞死亡。KSQ-4279是一种USP1抑制剂，目前正在I期试验中作为单一疗法或与PARP抑制剂或铂类化疗联合使用进行测试。 Werner综合征ATP-依赖性解旋酶（WRN）功能的丧失与癌细胞中的微卫星不稳定性-高（MSI-H）表型具有合成致死关系。WRN敲除已被证明会在MSI-H细胞中诱导广泛的DSBs、细胞周期失调、基因组不稳定和凋亡，但在体外微卫星稳定细胞中不会诱导。WRN抑制剂HRO761和RO7589831均已进入I期临床试验。 靶向合成致死代谢依赖性 代谢重编程是癌症的标志，肿瘤代谢的遗传或表观遗传改变，是调节细胞内自由基积累和维持肿瘤进展所需的生物合成和能量需求增加所必需的。甲硫基腺苷磷酸化酶（MTAP）缺失与PRMT5-MAT2A-RIOK1轴成分耗竭之间具有合成致死关系。MTAP的损失导致5′-甲硫腺苷（MTA）的积累，MTA本身通过竞争PRMT5 S-腺苷甲硫氨酸（SAM）结合袋，成为PRMT5的强效和选择性内源性抑制剂。因此，缺乏MTAP功能的细胞PRMT5甲基化水平降低，对进一步的PRMT5耗竭敏感，导致细胞生长抑制。目前正在临床试验中测试几种MTA协同PRMT5抑制剂，如AMG193、MRTX1719和TNG908，以及MAT2A抑制剂IDE397。 涉及代谢途径的合成致死相互作用还包括氨基酸和核酸代谢途径中的合成剂量致死性关系。例如，FLT3内部串联重复（FLT3-ITDs）是驱动因素，通过激活参与从头丝氨酸生物合成基因的转录因子4（ATF4）依赖性转录调控，赋予丝氨酸生物合成独特的代谢依赖性。在这种情况下，抑制丝氨酸生物合成中第一个也是唯一的限速酶磷酸甘油酸脱氢酶（PHGDH），使用PHGDH抑制剂WQ-2101在FLT3野生型细胞中亚致死的剂量，会导致凋亡诱导。与FLT3野生型细胞系相比，对携带FLT3-ITD突变的细胞系具有显著的抗增殖作用。 靶向表观遗传调控的合成致死策略 染色质调节过程的动态控制对细胞功能至关重要。在多达50%的癌症中检测到与读取、添加或删除表观遗传修饰以及影响染色质调节和组织有关的基因突变。SWI/SNF染色质重塑复合物（CRC）是四个ATP依赖性CRC家族之一，能够通过驱逐、动员或沉积核小体来改变染色质结构。编码SWI/SNF成分的基因突变大多导致功能丧失，在所有人类癌症中发生率高达20%。功能基因组筛查已证明SWI/SNF同源对SMARCA4-SMARCA2、ARID1A-ARID1B、SMARCA4-AMARCB1、SMARCA4-ARID2、SMARCA-4-ACTB和SMARCC1-SMARCC2之间存在合成致死相互作用。 作为表观遗传合成剂量致死性的另一个例子，研究发现SWI/SNF-BRG1-SMARCA4复合物在弥漫性中线胶质瘤患者中与H3K27M突变的表观遗传依赖性。SMARCA4与SOX10在H3K27M突变胶质瘤细胞的调节元件上共定位，以调节参与细胞增殖和细胞外基质的基因表达。H3K27M的功能缺失导致SMARCA4染色质在SOX10和H3K27乙酰化标记的增强子上的结合减少。使用靶向蛋白降解剂或小分子抑制剂靶向SMARCA4，在体外和体内模型中产生了抗肿瘤活性。 小结 合成致死作为一种新兴的肿瘤治疗策略，近年来备受关注。它基于两个非致死性基因同时受到抑制或干扰时，会导致细胞死亡的现象。合成致死的发现为癌症治疗提供了新的思路，推动了相关药物的开发。在合成致死策略中，PARP抑制剂是最成功的案例之一，PARP抑制剂通过抑制PARP的活性，导致DNA损伤无法修复，从而引起肿瘤细胞死亡。目前，PARP抑制剂已被批准用于治疗携带BRCA1或BRCA2基因突变的乳腺癌和卵巢癌。 除了PARP抑制剂，研究人员还在积极探索其他合成致死靶点，如ATR、PRMT5等。这些靶点的抑制剂在克服肿瘤耐药性、提高治疗效果方面显示出良好的潜力。与此同时，人们也正试图通过联合用药策略，如将PARP抑制剂与其他抗肿瘤药物联用，以提高治疗效果。总之，合成致死作为一种具有前景的肿瘤治疗策略，为癌症患者带来了新的希望。随着科研技术的不断发展，相信未来会有更多基于合成致死原理的新型抗肿瘤药物问世，为癌症治疗带来革命性的变革。 参考文献： 1.Synthetic lethal strategies for the development of cancer therapeutics. Nat Rev Clin Oncol.2025 Jan;22(1): 公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！ 公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。

Over the past three decenniums, the perception to treat cancer malignancies has improved from the time when the scientist and researches discovered the idea of inhibitors. The inhibitors are the novel class of chemotherapy which helps to block the activity of gene or protein by consequently binding to it. Since then, many therapies such as targeted antibody regimen, innovative chemotherapy drugs, oncolytic virus therapy, cancer vaccines, stem cell transplant, in addition to surgery has entered the commercial market with the primary motive is to provide treatment for endless patients suffering from cancer. Nevertheless, with the advancement together with evolution in the immunotherapy has led to the development of various inhibitors in the sector of oncology therapy. One such inhibitor is CDC 7 kinase inhibitor used to manage several types of solid cancer such as colon cancer, ovarian cancer, prostate cancer, as well as pancreas cancer in addition to blood cancer like leukemias. Download Global CDC7 Kinase Inhibitors Clinical Trials Research With the arrival of CDC 7 kinase inhibitor as an innovative treatment regimen has somewhat aided to reduce the cancer burden of multiple patients across the world. Preliminary data from the clinical and laboratories studies have illustrated the over expression of CDC 7 kinase protein results in the formation to tumor cell. One of the foremost causes for development of cancer is the mutation in CDC gene that encodes protein, CDC 7 involved in the process of DNA replication. As an outcome, mutation in CDC 7 encoding gene led to the formation of over expression of CDC 7 protein in conjugation with its protein regulator Dbf4. The year 2009 was a blessing for the domain of CDC 7 kinase inhibitor owing to the introduction of first CDC 7 kinase inhibitor, BMS-863233/ XL 413 for the treatment of patients suffering from advanced solid cancers, metastatic cancer along with refractory hematologic cancer. The initial studies was sponsored and collaborated by Bristol Myers Squibb in addition to Exelixis. However, the clinical trial was terminated at the phase I stage in the year 2011 on the account of multiple reasons such as the presence of a accumulated metabolite, buildup of the parent drug at very high levels owing to patients populace that had a poor metabolizer (PM) phenotype in addition to identification of CYP1A2 enzyme that is involved in the metabolism of the parent compound and lack of clinical efficacy. As a consequence, the candidate couldn’t proceed to phase II clinical phase stage. Nonetheless, lately in the year 2023, the contender, BMS- 863233 is also being used with chemotherapy which has correspondingly demonstrated positive outcome by significantly inhibiting cancer cell growth. Apart from utilizing the CDC 7 kinase inhibitor therapy to cure cancer malignancies, several additional studies are ongoing in the recent year which demonstrates the role of CDC 7 kinase protein in inducing viral replication, consequently leading to the development of viral infection by phosphorylating VP3 protein of the Avibirnavirus, which belongs to the family of Birnaviridae. For that reason, the CDC 7 kinase protein can be employed against cancer majorly solid malignancies as well as viral infection indications. The domain of CDC 7 kinase inhibitor is growing at a slow; but steady gait. Due to the presence of pharmaceutical companies such as Bristol-Myers Squibb, Exelixis, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nerviano Medical Sciences, Takeda (Millennium Pharmaceuticals, Inc.) and Lin BioScience, Inc in addition to various centers and universities which include University Of Miami, Massachusetts General Hospital, Dana-Farber Cancer Institute, Tianjin Medical University Cancer Institution & Hospital are conducting clinical research in the domain with the primary purpose to developed an advance and innovative inhibitor that will target CDC 7 kinase protein in order to provide treatment for ovarian cancer, prostate cancer, solid tumor, Refractory Hematologic Cancer, Metastatic Cancer, Colorectal Cancer etc. Hitherto, only a smattering of preclinical and clinical trials is ongoing in the domain. Candidates such as LY3143921 hydrate and SGR-2921 are presently in the phase I clinical trial for the purpose to provide treatment for several cancer indications such as advanced/metastatic solid tumors, refractory hematologic cancer, colorectal cancer, high grade serous ovarian cancer in addition to non-small cell lung cancer (squamous cell variant). Apart from that, recently in the year 2023, contenders such as TQB3824 tablets, LBS-007 in conjugation with TAK-931 are the novel candidates that have been added into the global clinical pipeline for CDC 7 inhibitors. TAK-931 is the solitary medication that has reached the phase II clinical stage to treat advanced non hematologic neoplasms and at present the clinical investigations and studies are ongoing in Japan. All these example aforementioned above propose that the domain of CDC 7 inhibitor is growing and shortly will expand further owing to the increasing cancer and viral diseases indications and rise in the technological advancement.