The protein kinase ataxia telangiectasia mutated (ATM) is a constituent of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, exerting a pivotal influence on diverse cellular processes, notably the signaling of double-strand DNA breaks (DSB) and stress response. The dysregulation of ATM is implicated in the pathogenesis of cancer and other diseases such as neurodegeneration. Hence, ATM is deemed a promising candidate for potential therapeutic interventions across a spectrum of diseases. Presently, while ATM small molecule inhibitors are not commercially available, various selective inhibitors have progressed to the clinical research phase. Specifically, AZD1390, WSD0628, SYH2051, and ZN-B-2262 are under investigation in clinical studies pertaining to glioblastoma multiforme and advanced solid tumors, respectively. In this Perspective, we encapsulate the structure, biological functions, and disease relevance of ATM. Subsequently, we concentrate on the design concepts and structure-activity relationships (SAR) of ATM inhibitors, delineating potential avenues for the development of more efficacious ATM-targeted inhibitors.

2024-08-01·Journal of Pharmacology and Experimental Therapeutics

Preclinical Systemic Pharmacokinetics, Dose Proportionality, and Central Nervous System Distribution of the ATM Inhibitor WSD0628, a Novel Radiosensitizer for the Treatment of Brain Tumors

Article

作者: Zhang, Wenjuan ; Garcia, Darwin A ; Zhong, Wei ; Le, Jiayan ; Oh, Ju-Hee ; Mladek, Ann C ; Sarkaria, Jann N ; Xue, Zhiyi ; Zhang, Wenqiu ; Elmquist, William F ; Rathi, Sneha ; Burgenske, Danielle M

Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier. The objective of this study was to evaluate the systemic pharmacokinetics and mechanisms that influence the central nervous system (CNS) distribution of WSD0628, a novel and potent ATM inhibitor, in the mouse. Further, we have used these observations to form the basis of predicting effective exposures for clinical application. We observed a greater than dose proportional increase in exposure, likely due to saturation of clearance processes. Our results show that WSD0628 is orally bioavailable and CNS penetrant, with unbound partitioning in CNS (i.e., unbound tissue partition coefficient) between 0.15 and 0.3. CNS distribution is not limited by the efflux transporters P-glycoprotein and breast cancer resistant protein. WSD0628 is distributed uniformly among different brain regions. Thus, WSD0628 has favorable pharmacokinetic properties and potential for further exploration to determine the pharmacodynamics-pharmacokinetics efficacy relationship in CNS tumors. This approach will provide critical insights for the clinical translation of WSD0628 for the treatment of primary and secondary brain tumors. SIGNIFICANCE STATEMENT: This study evaluates the preclinical systemic pharmacokinetics, dose proportionality, and mechanisms influencing CNS distribution of WSD0628, a novel ATM inhibitor for the treatment of brain tumors. Results indicate that WSD0628 is orally bioavailable and CNS penetrant without efflux transporter liability. We also observed a greater than dose proportional increase in exposure in both the plasma and brain. These favorable pharmacokinetic properties indicate WSD0628 has potential for further exploration for use as a radiosensitizer in the treatment of brain tumors.

2012-05-01·Breast Cancer Research and Treatment2区 · 医学

Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor

2区 · 医学

Article

作者: Yan Zhang ; Xianke Zeng ; Douglas Yee ; Annabell Oh ; Hua Zhang

The type I insulin-like growth factor receptor (IGF1R) contributes to cancer cell biology. Disruption of IGF1R signaling alone or in combination with cytotoxic agents has emerged as a new therapeutic strategy. Our laboratory has shown that sequential treatment with doxorubicin (DOX) and anti-IGF1R antibodies significantly enhanced the response to chemotherapy. In this study, we examined whether inhibition of the tyrosine kinase activity of this receptor family would also enhance chemotherapy response. Cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) inhibited IGF1R and insulin receptor (InsR) kinase activity and downstream activation of ERK1/2 and Akt in MCF-7 and LCC6 cancer cells. PQIP inhibited both monolayer growth and anchorage-independent growth in a dose-dependent manner. PQIP did not induce apoptosis, but rather, PQIP treatment was associated with an increase in autophagy. We examined whether sequential or combination therapy of PQIP with DOX could enhance growth inhibition. PQIP treatment together with DOX or DOX followed by PQIP significantly inhibited anchorage-independent growth in MCF-7 and LCC6 cells compared to single agent alone. In contrast, pre-treatment with PQIP followed by DOX did not enhance the cytotoxicity of DOX in vitro. Furthermore, OSI-906, a PQIP derivative, inhibited IGF-I signaling in LCC6 xenograft tumors in vivo. When given once a week, simultaneous administration of OSI-906 and DOX significantly enhanced the anti-tumor effect of DOX. In summary, these results suggest that timing and duration of the IGF1R/InsR tyrosine kinase inhibitors with chemotherapeutic agents should be evaluated in clinical trials. Long-term disruption of IGF1R/InsR may not be necessary when combined with cytotoxic chemotherapy.

项与 WSD-0628 相关的新闻（医药）

2024-09-05

·医药观澜

具有穿透血脑屏障潜力！威尚生物新型EGFR抑制剂1/2期临床试验完成中国首例受试者入组

▎药明康德内容团队报道今日（9月4日），威尚生物医药宣布其新型EGFR抑制剂WSD0922在上海东方医院周彩存教授带领下完成首例受试者入组。今年7月8日，WSD0922获中国国家药监局（NMPA）批准该在研产品在中国开展1期桥接及2期扩展临床试验，用于经一线三代EGFR抑制剂治疗进展具C797S突变的晚期/转移性非小细胞肺癌。 WSD0922是威尚生物研发的一款具有穿透血脑屏障潜力的第四代EGFR/EGFRvIII靶向抑制剂，拟开发适应症为非小细胞肺癌神经中枢转移及脑部肿瘤。根据威尚生物医药新闻稿，该药具有克服多种一线三代EGFR抑制剂耐药机制的潜力，特别是具有C797S耐药突变患者，并可用于治疗EGFRvIII驱动的脑胶质母细胞瘤（GBM）和间变型胶质瘤（AA）。 “非常高兴WSD0922完成在中国的1/2期临床试验用于经一线三代EGFR抑制剂包括奥希替尼，伏美替尼，阿美替尼和贝福替尼治疗进展具C797S突变的晚期/转移性非小细胞肺癌首例受试者入组，这对中国加入正在进行的非小细胞肺癌经一线奥希替尼治疗进展具C797S的国际多中心2期临床试验具有重要意义”，威尚生物医药CEO兼创始人钟卫博士说，“WSD0922在美国妙佑医疗国际（Mayo Clinic）已完成的临床1期剂量爬升及正在进行的扩展队列中对经奥希替尼治疗后非小细胞肺癌神经中枢转移及复发脑胶质瘤展现了良好的PK及安全性，特别是在经奥希替尼治疗后具有C797S突变的非小细胞肺癌脑转移/脑膜转移病人和EGFRvIII的复发脑胶质瘤患者中显示了令人振奋的初步疗效。期待WSD0922能早日解决一线三代EGFR抑制剂耐药具C797S突变的未满足临床需求“。威尚生物专注于未满足临床需求的脑部肿瘤靶向药物研发。除了WSD0922，该公司正在开发更多管线产品。WSD0628是一款能穿透血脑屏障的ATM靶向抑制剂，拟开发联合放疗用于脑部肿瘤，目前正在美国开展1期及2a期临床试验，并获得NCI U19及FDA ODD R01基金支持。另一款候选药物WSD1227目前处于临床申报准备阶段，拟单药或联合用药治疗脑部肿瘤。参考资料：[1]威尚生物新闻稿本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

临床1期临床2期临床终止

2024-07-08

·医药观澜

具有穿透血脑屏障潜力！威尚生物新型EGFR抑制剂获中国NMPA批准1/2期临床

今日（7月8日），威尚生物医药宣布，中国国家药监局（NMPA）已批准其新型EGFR抑制剂WSD0922在中国开展1期桥接及2期扩展临床试验，用于经一线三代EGFR抑制剂（包括奥希替尼，伏美替尼，阿美替尼和贝福替尼）治疗进展具C797S突变的晚期/转移性非小细胞肺癌。根据威尚生物医药新闻稿，WSD0922是该公司自主研发的一款具有穿透血脑屏障潜力的第四代EGFR/EGFRvIII靶向抑制剂，拟开发适应症为非小细胞肺癌神经中枢转移及脑部肿瘤。该药具有克服多种一线三代EGFR抑制剂耐药机制的潜力，并可用于治疗EGFRvIII驱动的脑胶质母细胞瘤（GBM）和间变型胶质瘤（AA）。本次获批的是一项评估WSD0922-FU治疗晚期非小细胞肺癌的安全性、耐受性、药代动力学和有效性的多中心、开放、单臂1/2期临床研究，旨在评估WSD0922治疗接受三代EGFR 抑制剂一线治疗后出现疾病进展且具有EGFR基因C797S突变的晚期或转移性非小细胞肺癌患者的疗效和安全性。该试验由周彩存教授作为牵头研究者，将在约20家临床中心开展。 “我们很荣幸中国药监局接受了WSD0922在中国的1/2期临床试验申请用于经一线三代EGFR 抑制剂包括奥希替尼，伏美替尼，阿美替尼和贝福替尼治疗进展具C797S突变的晚期/转移性非小细胞肺癌，这是WSD0922在中国的临床开发具有里程碑意义的一步”，威尚生物医药CEO兼创始人钟卫博士说，“WSD0922在美国妙佑医疗国际（Mayo Clinic）已完成的临床1期剂量爬升及正在进行的扩展队列中对经奥希替尼治疗后非小细胞肺癌神经中枢转移及复发脑胶质瘤展现了良好的PK及安全性，特别是在经奥希替尼治疗后具有C797S突变的非小细胞肺癌脑转移/脑膜转移病人和EGFRvIII的复发脑胶质瘤患者中显示了令人振奋的初步疗效。本次中国的1/2期临床试验将奠定中国加入美国FDA 已获批的WSD0922用于一线奥希替尼进展具C797S突变的晚期/转移性非小细胞肺癌的国际多中心2期临床试验的基础。期待WSD0922能早日解决一线三代EGFR抑制剂耐药具C797S突变的未满足临床需求“。威尚生物专注于未满足临床需求的脑部肿瘤靶向药物研发。除了WSD0922，该公司开发的WSD0628是一款能穿透血脑屏障的ATM靶向抑制剂，拟开发联合放疗用于脑部肿瘤，目前已经得到FDA临床批件在美国开展1期及2a期临床试验，并获得NCI U19及FDA ODD R01基金支持。此外，该公司还有一些策略性研发管线，以WSD1227为例，该药可以单药或联合用药治疗脑部肿瘤，目前在临床前IND准备阶段。参考资料：[1]威尚生物新闻稿内容来源于网络，如有侵权，请联系删除。

临床2期申请上市

2024-05-28

·医药观澜

具有穿透血脑屏障潜力！威尚生物新型EGFR抑制剂获FDA批准2期临床

5月27日，威尚生物医药宣布FDA批准其新型EGFR抑制剂WSD0922在美国开展2期临床试验，用于经一线奥希替尼治疗进展具C797S突变的晚期/转移性非小细胞肺癌。根据威尚生物医药新闻稿，WSD0922是该公司自主研发的一款具有穿透血脑屏障潜力的第四代EGFR/EGFRvIII靶向抑制剂，拟开发适应症为非小细胞肺癌神经中枢转移及脑部肿瘤。该药具有克服多种一线奥希替尼耐药机制的潜力，并可用于治疗EGFRvIII驱动的脑胶质母细胞瘤（GBM）和间变型胶质瘤（AA）。本次获批的是一项开放标签、单臂、国际多中心2期临床试验，旨在评估WSD0922治疗接受奥希替尼一线治疗后出现疾病进展且具有EGFR基因C797S突变的晚期或转移性非小细胞肺癌患者的疗效和安全性。该试验将在中国、美国、法国、加拿大约20家临床中心开展。 “我们很荣幸FDA接受了WSD0922在美国的2期临床试验申请用于经一线奥希替尼治疗进展具C797S突变的晚期/转移性非小细胞肺癌，这是具有里程碑意义的一步”，威尚生物医药CEO兼创始人钟卫博士说，“WSD0922在已完成的临床1期剂量爬升及正在进行的扩展队列中对经奥希替尼治疗后非小细胞肺癌神经中枢转移及复发脑胶质瘤展现了良好的PK及安全性，特别是在经奥希替尼治疗后具有C797S突变的非小细胞肺癌脑转移/脑膜转移病人和EGFRvIII的复发脑胶质瘤患者中显示了令人振奋的初步疗效。本次国际多中心2期临床试验将奠定WSD0922建立标准二线/三线治疗方案用于一线奥希替尼进展具C797S突变的晚期/转移性非小细胞肺癌的坚实基础。感谢FDA在评审中给予的支持与帮助，期待WSD0922能早日解决一线奥希替尼耐药具C797S突变的未满足临床需求“。威尚生物专注于未满足临床需求的脑部肿瘤靶向药物研发。除了WSD0922，该公司开发的WSD0628是一款能穿透血脑屏障的ATM靶向抑制剂，拟开发联合放疗用于脑部肿瘤，目前已经得到FDA临床批件在美国开展1期及2a期临床试验，并获得NCI U19及FDA ODD R01基金支持。此外，该公司还有一些策略性研发管线，以WSD1227为例，该药可以单药或联合用药治疗脑部肿瘤，目前在临床前IND准备阶段。内容来源于网络，如有侵权，请联系删除。