Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-299
M. Pitz, Alexandra Nukovic, M. Elpers, Sarah Wilde, Angela A Alexander-Bryant
Traditional treatment methods for glioblastoma multiforme (GBM) including resection, radiation, and chemotherapy have been largely unsuccessful, with a current 5-year survival rate of 5.6%. In this project we examine the potential of nanosized self-assembling peptide hydrogels to locally deliver and convert temozolomide (TMZ), an FDA-approved pH-sensitive prodrug, for GBM treatment. The peptide hydrogel is designed to load TMZ into the hydrophobic regions of the hydrogels, and during hydrogel degradation in vivo, convert TMZ into its active form. Hydrogel characterization, drug loading and conversion, and cellular uptake and viability are examined to determine the in vitro efficacy of this delivery method. A combination of dynamic light scattering (DLS), scanning electron microscopy (SEM), and circular dichroism (CD) are used to characterize size and structure of the hydrogels. Loading and conversion of TMZ are quantified using UV-Vis spectroscopy. Fluorescent imaging and cell viability assays are used to determine uptake and anti-cancer effects of the drug-loaded hydrogels on glioblastoma cells. Our results show high uptake in drug-resistant T98G and non-resistant LN-18 glioblastoma cell lines using several of our tunable peptide formulations. CD has shown that all peptide formulations form mostly beta-sheet and random structures during self-assembly. SEM and DLS show that peptide hydrogels formed in a water solvent are more polydisperse than hydrogels in a PBS solvent. Using a pH-meter, we have shown that as the peptides in PBS degrade, there is an increase in local pH. Additionally, TMZ conversion is observed to occur more quickly in drug-loaded hydrogels than TMZ alone. Preliminary cell viability studies have shown that unassembled peptides are not cytotoxic; some of the assembled peptide hydrogels are cytotoxic while others maintain greater than 80% viability when compared to untreated cells. Future studies for the project will include cell viability assays with the most promising peptide formulations loaded with TMZ to determine efficacy of the delivery and conversion system. Finally, this project will culminate in an in vivo study to confirm the overall anti-cancer effect of the drug-loaded peptide hydrogels in a tumor model of GBM. Acknowledgements: This research was supported in part by the National Science Foundation EPSCoR Program under NSF Award # OIA-1655740, the National Institute of Health Award # P30GM131959, and National Science Foundation9s Graduate Research Fellowship Program. Citation Format: Megan Pitz, Alexandra Nukovic, Margaret Elpers, Sarah Wilde, Angela Alexander-Bryant. Self-assembling peptide hydrogel for delivery and conversion of temozolomide in glioblastoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 299.
多形性胶质母细胞瘤(GBM)的传统治疗方法包括切除、放疗和化疗，在很大程度上是不成功的，目前的5年生存率为5.6%。在这个项目中，我们研究了纳米级自组装肽水凝胶局部递送和转化替莫唑胺(TMZ)的潜力，替莫唑胺是一种经fda批准的ph敏感前药，用于治疗GBM。肽水凝胶被设计成将TMZ装载到水凝胶的疏水区域，并在水凝胶的体内降解过程中将TMZ转化为活性形式。考察了水凝胶表征、药物装载和转化、细胞摄取和活力，以确定这种递送方法的体外功效。采用动态光散射(DLS)、扫描电子显微镜(SEM)和圆二色性(CD)相结合的方法表征了水凝胶的大小和结构。利用紫外可见光谱对TMZ的加载和转化进行了定量分析。荧光成像和细胞活力测定用于确定载药水凝胶对胶质母细胞瘤细胞的摄取和抗癌作用。我们的研究结果显示，使用我们的几种可调肽制剂，耐药T98G和非耐药LN-18胶质母细胞瘤细胞系的摄取很高。CD表明，所有的肽制剂在自组装过程中大多形成β -片和随机结构。SEM和DLS表明，在水溶剂中形成的肽凝胶比在PBS溶剂中形成的肽凝胶更具多分散性。使用ph计，我们发现随着PBS中的肽降解，局部ph值增加。此外，在载药水凝胶中观察到TMZ的转化比单独的TMZ更快。初步的细胞活力研究表明，未组装的肽没有细胞毒性;与未经处理的细胞相比，一些组装的肽水凝胶具有细胞毒性，而另一些则保持80%以上的活力。该项目未来的研究将包括用最有希望的装载TMZ的肽制剂进行细胞活力测定，以确定传递和转化系统的功效。最后，该项目将在体内研究中达到高潮，以确认载药肽水凝胶在GBM肿瘤模型中的整体抗癌作用。致谢:本研究得到了美国国家科学基金会EPSCoR项目(NSF奖# OIA-1655740)、美国国立卫生研究院奖# P30GM131959和美国国家科学基金会研究生研究奖学金项目的部分支持。引文格式:Megan Pitz, Alexandra Nukovic, Margaret Elpers, Sarah Wilde, Angela Alexander-Bryant。替莫唑胺在胶质母细胞瘤治疗中的传递和转化的自组装肽水凝胶[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):299。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-283
Lindsay Bourdeau, Carlos Cruz, Taylor Williams
One of the rarest and most aggressive pediatric cancers to date is the malignant rhabdoid tumor (MRT), maintaining a survival rate of 16%. Considered a renal cancer, approximately 20-25 new cases are diagnosed in the USA each year, with the average age of diagnosis being about 11 months old. Conventional strategies for treating MRT are limited due to several factors including off-target associated toxicities, patient population, age, metastasis to brain tissue, and diminished survival rates. CLENs (cell membrane lipid-extracted nanoliposomes), a novel drug delivery system, was previously developed and evaluated for selective delivery of cytotoxic drug agents to breast cancer cells and compared to more conventional liposomes. The purpose of this investigation was to optimize and characterize G401-CLENs for selective targeting and delivery of model payloads to a cellular model of rhabdoid tumors. The MRT cell line (G-401 [G401] (ATCC® CRL-1441™) was cultured in McCoy9s 5A Medium (ATCC® 30-2007™), supplemented by 10% FBS. The G401 cellular lipid materials (otherwise known as lipid extracts (LE)) were derived from G401 cells. Follow up studies include the incorporation of G401-LE in liposomes to form G401-CLENs. For development, special consideration was given to distinct determinants of targeting (i.e., particle size and zeta potential) and cellular uptake by G401-CLENs. Other analyses include a comparison of delivery of model and functional siRNA (BRD9 Silencer Select Pre-designed, siRNA ID s35295, Ambion) to G401 target cells using G401-CLENs, and conventional nano-preparations in vitro. G401-LE cell membrane components were extracted from rhabdoid G401 cells. On-going physiochemical characterization studies of G401-CLENs and functional in vitro and fluorescence microscopic analyses are currently underway. Citation Format: Lindsay Bourdeau, Carlos Cruz, Taylor Williams. Target cell-derived, G401-CLENs for selective delivery of model therapeutics to rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 283.
恶性横纹肌样瘤(MRT)是迄今为止最罕见和最具侵袭性的儿科癌症之一，其生存率为16%。被认为是肾癌，在美国每年大约有20-25例新诊断病例，平均诊断年龄约为11个月大。由于多种因素，包括脱靶相关毒性、患者群体、年龄、脑组织转移和生存率降低，治疗MRT的传统策略受到限制。CLENs(细胞膜脂质提取纳米脂质体)是一种新型的药物递送系统，先前已被开发并评估用于选择性递送细胞毒性药物到乳腺癌细胞，并与更传统的脂质体进行比较。本研究的目的是优化和表征G401-CLENs选择性靶向并将模型有效载荷递送到横纹肌样肿瘤细胞模型。将MRT细胞系G-401 [G401] (ATCC®CRL-1441™)培养于McCoy9s 5A培养基(ATCC®30-2007™)中，添加10%胎牛血清。G401细胞脂质物质(也称为脂质提取物(LE))来源于G401细胞。后续研究包括在脂质体中掺入G401-LE形成G401-CLENs。为了开发，特别考虑了G401-CLENs的靶向性(即粒径和zeta电位)和细胞摄取的不同决定因素。其他分析包括使用G401- clens和常规纳米制剂将模型siRNA和功能性siRNA (BRD9 Silencer Select Pre-designed, siRNA ID s35295, Ambion)递送到G401靶细胞的比较。从横纹肌样G401细胞中提取G401- le细胞膜成分。目前正在进行G401-CLENs的理化特性研究以及体外功能和荧光显微镜分析。引文格式:Lindsay Bourdeau, Carlos Cruz, Taylor Williams。靶细胞衍生的G401-CLENs用于横纹肌样肿瘤模型疗法的选择性递送[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):摘要第283期。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-281
K. L. Alatise, S. Gardner, Angela A Alexander-Bryant
Introduction: With a 5-year survival rate of 47%, ovarian cancer is the 5th leading cause of death amongst women worldwide. Over 75% of patients experience recurrence after initial treatment, indicating a need for improved treatment options. Drug resistance is a major barrier hindering the success of current treatment methods. Our study analyzes the characteristics of a stimuli-sensitive liposomal delivery system for combatting drug resistance. Our delivery system will deliver bioactive siRNAs targeting genes related to drug resistance, cell proliferation, and apoptosis. In this study, we investigate the characteristics of the liposomes to determine particle size, surface charge, and ability to encapsulate/bind both siRNAs. We also begin to investigate the delivery potential of the pH-sensitive liposomal formulation in vitro using ovarian cancer cell lines. Methods: Empty and siRNA loaded cationic, pH-sensitive liposomes (CHEMS-LPs) were synthesized by the thin-film hydration method. Liposome size, zeta potential, and polydispersity index (PDI) were measured by dynamic light scattering (DLS). To measure siRNA encapsulation efficiency, fluorescently labeled siRNA was loaded into CHEMS-LPs and subjected to centrifugation to pellet the LPs. Fluorescence spectroscopy was used to detect siRNA in the supernatant. The toxicity of unloaded CHEMS-LPs was determined by an MTS assay using OVCAR3 (drug-sensitive) and OVCAR3-T40 (drug-resistant) human ovarian cancer cells. Results: The size and zeta potential of blank and siRNA-loaded CHEMS-LPs were 97.88 ± 2.39 nm and 29.0 ± 2.00 mV, and 80.78 ± 0.77 nm and 13.1 ±1.66 mV, respectively. The positively charged zeta potential confirms the cationic nature of our liposomes. The PDI demonstrated that the liposomes were unimodal and monodisperse with PDI values of less than 0.300 for each formulation. In addition, siRNA was successfully bound to CHEMS-LPs through electrostatic interaction with the cationic lipid layer, resulting in an encapsulation efficiency of 99.6% Conclusion: CHEMS-LPs are pH-sensitive, cationic, monodisperse liposomes able to encapsulate siRNAs in order to mediate delivery into ovarian cancer cells. Their stable structure, positive charge, and low cytotoxicity is promising for future studies, including delivery of bioactive siRNAs to stimulate downregulation of target genes related to drug resistance. Acknowledgements: This work was supported in part by the National Science Foundation EPSCoR Program under Award # OIA-1655740. We would like to thank George Duran from Stanford University for donating the OVCAR3-T40 cell line. Citation Format: Kharimat Lora Alatise, Samantha Gardner, Angela Alexander-Bryant. pH-sensitive liposome for siRNA delivery to treat drug-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 281.
{"title":"Abstract 281: pH-sensitive liposome for siRNA delivery to treat drug-resistant ovarian cancer","authors":"K. L. Alatise, S. Gardner, Angela A Alexander-Bryant","doi":"10.1158/1538-7445.AM2021-281","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-281","url":null,"abstract":"Introduction: With a 5-year survival rate of 47%, ovarian cancer is the 5th leading cause of death amongst women worldwide. Over 75% of patients experience recurrence after initial treatment, indicating a need for improved treatment options. Drug resistance is a major barrier hindering the success of current treatment methods. Our study analyzes the characteristics of a stimuli-sensitive liposomal delivery system for combatting drug resistance. Our delivery system will deliver bioactive siRNAs targeting genes related to drug resistance, cell proliferation, and apoptosis. In this study, we investigate the characteristics of the liposomes to determine particle size, surface charge, and ability to encapsulate/bind both siRNAs. We also begin to investigate the delivery potential of the pH-sensitive liposomal formulation in vitro using ovarian cancer cell lines. Methods: Empty and siRNA loaded cationic, pH-sensitive liposomes (CHEMS-LPs) were synthesized by the thin-film hydration method. Liposome size, zeta potential, and polydispersity index (PDI) were measured by dynamic light scattering (DLS). To measure siRNA encapsulation efficiency, fluorescently labeled siRNA was loaded into CHEMS-LPs and subjected to centrifugation to pellet the LPs. Fluorescence spectroscopy was used to detect siRNA in the supernatant. The toxicity of unloaded CHEMS-LPs was determined by an MTS assay using OVCAR3 (drug-sensitive) and OVCAR3-T40 (drug-resistant) human ovarian cancer cells. Results: The size and zeta potential of blank and siRNA-loaded CHEMS-LPs were 97.88 ± 2.39 nm and 29.0 ± 2.00 mV, and 80.78 ± 0.77 nm and 13.1 ±1.66 mV, respectively. The positively charged zeta potential confirms the cationic nature of our liposomes. The PDI demonstrated that the liposomes were unimodal and monodisperse with PDI values of less than 0.300 for each formulation. In addition, siRNA was successfully bound to CHEMS-LPs through electrostatic interaction with the cationic lipid layer, resulting in an encapsulation efficiency of 99.6% Conclusion: CHEMS-LPs are pH-sensitive, cationic, monodisperse liposomes able to encapsulate siRNAs in order to mediate delivery into ovarian cancer cells. Their stable structure, positive charge, and low cytotoxicity is promising for future studies, including delivery of bioactive siRNAs to stimulate downregulation of target genes related to drug resistance. Acknowledgements: This work was supported in part by the National Science Foundation EPSCoR Program under Award # OIA-1655740. We would like to thank George Duran from Stanford University for donating the OVCAR3-T40 cell line. Citation Format: Kharimat Lora Alatise, Samantha Gardner, Angela Alexander-Bryant. pH-sensitive liposome for siRNA delivery to treat drug-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 281.","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74927680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-321
Z. Chen, Zhengjia Chen, Chao Zhang, Jianhong Chen, Dongsheng Wang, N. Saba, Zhong Chen
{"title":"Abstract 321: Identification of proteins associated withFAT1mutations which potentially contribute to oncogenesis and progression of head and neck cancers","authors":"Z. Chen, Zhengjia Chen, Chao Zhang, Jianhong Chen, Dongsheng Wang, N. Saba, Zhong Chen","doi":"10.1158/1538-7445.AM2021-321","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-321","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74976920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-290
M. G. Ibañez, A. Giménez-Capitán, Marta Vives Usano, R. R. Lladó, S. Rodríguez, E. Aldeguer, B. G. Peláez, N. J. Ariza, C. Aguado, S. Viteri, A. Aguilar, I. Moya, C. Cabrera, M. Catalan, M. G. Cao, S. García-Román, Jordi Bertran Alamillo, F. G. Casabal, R. Rosell, M. Molina-Vila, C. D. L. Casas
{"title":"Abstract 290: Comparison of clinically relevant fusions detection using two multiplexing RNA based platforms: nCounter and GeneReader","authors":"M. G. Ibañez, A. Giménez-Capitán, Marta Vives Usano, R. R. Lladó, S. Rodríguez, E. Aldeguer, B. G. Peláez, N. J. Ariza, C. Aguado, S. Viteri, A. Aguilar, I. Moya, C. Cabrera, M. Catalan, M. G. Cao, S. García-Román, Jordi Bertran Alamillo, F. G. Casabal, R. Rosell, M. Molina-Vila, C. D. L. Casas","doi":"10.1158/1538-7445.AM2021-290","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-290","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72765942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-293
Chiara Borsari, Erhan Keles, A. Treyer, Martina De Pascale, P. Hebeisen, M. Hamburger, M. Wymann
{"title":"Abstract 293: Second-generation tricyclic pyrimido-pyrrolo-oxazine mTOR inhibitors suitable for the treatment of CNS disorders","authors":"Chiara Borsari, Erhan Keles, A. Treyer, Martina De Pascale, P. Hebeisen, M. Hamburger, M. Wymann","doi":"10.1158/1538-7445.AM2021-293","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-293","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79368948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-322
A. Olajuyin, A. Olajuyin, Ziqi Wang, Zhiwei Xu, Hayatu Raji, M. Okeke, Xiaoju Zhang
{"title":"Abstract 322: Protein expression shift and potential diagnostic markers through proteomics profiling of A549 lung cancer cells","authors":"A. Olajuyin, A. Olajuyin, Ziqi Wang, Zhiwei Xu, Hayatu Raji, M. Okeke, Xiaoju Zhang","doi":"10.1158/1538-7445.AM2021-322","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-322","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78731791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-269
C. Ayala-Orozco, Alexis van Venrooy, Dongdong Liu, Yewen Shi, J. L. Beckham, D. Izhaky, J. Tour, J. Myers, Roberto Rangel
{"title":"Abstract 269: Harnessing the mechanical power of nanomachines to treat cancer: Light-activated molecular nanomachines kill melanoma and oral cancer cells","authors":"C. Ayala-Orozco, Alexis van Venrooy, Dongdong Liu, Yewen Shi, J. L. Beckham, D. Izhaky, J. Tour, J. Myers, Roberto Rangel","doi":"10.1158/1538-7445.AM2021-269","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-269","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"79 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79287432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-271
Petra Paizs, M. Widlak, Á. Perdones-Montero, M. Sani, L. Ford, J. Alexander, Simon J. S. Cameron, R. Arasaradnam, J. Kinross, Z. Takáts
{"title":"Abstract 271: High-throughput fecal metabolic profiling for the early detection of colorectal cancer using a direct mass spectrometry assay","authors":"Petra Paizs, M. Widlak, Á. Perdones-Montero, M. Sani, L. Ford, J. Alexander, Simon J. S. Cameron, R. Arasaradnam, J. Kinross, Z. Takáts","doi":"10.1158/1538-7445.AM2021-271","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-271","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88238061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-326
L. Du, Jing Liu, Qinglong Zeng, M. Xu, Jiting Lu, Qiangang Zheng, Jidong Zhu
The Hippo pathway is an evolutionarily conserved pathway involved in developmental biology. The biological functions of Hippo pathway are executed by the downstream transcriptional coactivator YAP/TAZ, which shuttle between the cytoplasm and the nucleus and have to interact with TEADs in nucleus for transcription activation. YAP/TAZ are master transcriptional factors widely activated in human cancers to promote cancer initiation, progression, metastasis and therapy resistance. It has been shown that aberrant YAP/TAZ activation is also associated with the adapted tumor microenvironment (TME) for tumor growth. Dysregulation in Hippo pathway and YAP/TAZ-TEADs transcriptional activity is pervasively associated with various types of cancers, including mesothelioma, squamous cell cancers, liver cancer and lung cancer, making it an attractive target for cancer therapy. Therefore, inhibition of YAP/TAZ oncogenic activity by blocking YAP/TAZ-TEADs interaction is an effective approach for cancer treatment. In this study, we aim to discover small molecule inhibitors that bind to TEADs and disrupt YAP/TAZ-TEADs interaction for cancer therapy. With superposition of all the available crystal structures of four TEAD subtypes in the public database, we found the YAP Ω loop binding site of TEADs is relatively rigid (of backbone atoms), but the side chain flexibility of K289, K265 and V406 in TEAD1 affects the shape of the binding site significantly. Notably, in two TEAD2 structures, e.g. PDB ID: 5dqe and 5dq8, K301 (K274 of TEAD1) adopts an open conformation and accommodates a flufenamic acid to bind in an induced pocket. Using 5dq8 as the protein model, we virtually screened a fragment library, and identified a hit compound that is suitable to combine with flufenamic acid. Interaction between the hit compound and TEAD1 was confirmed by 1D-NMR (STD). Based on the docking poses, we combined the hit and flufenamic acid, designed and synthesized several compounds. Interaction with TEAD1 of the compounds were confirmed by 1D-NMR, SPR and HTRF. Crystal structures of representative compounds confirmed the predicted binding mode in TEAD1. With further medicinal chemistry efforts, we have discovered a series of novel YAP/TAZ-TEAD PPI inhibitors bound at the Ω loop site of TEAD1. Citation Format: Lin Du, Jing Liu, Qinglong Zeng, Ming Xu, Jiting Lu, Qiangang Zheng, Jidong Zhu. Structural dynamics-based hit generation to disrupt YAP/TAZ-TEAD protein-protein interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 326.
{"title":"Abstract 326: Structural dynamics-based hit generation to disrupt YAP/TAZ-TEAD protein-protein interaction","authors":"L. Du, Jing Liu, Qinglong Zeng, M. Xu, Jiting Lu, Qiangang Zheng, Jidong Zhu","doi":"10.1158/1538-7445.AM2021-326","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-326","url":null,"abstract":"The Hippo pathway is an evolutionarily conserved pathway involved in developmental biology. The biological functions of Hippo pathway are executed by the downstream transcriptional coactivator YAP/TAZ, which shuttle between the cytoplasm and the nucleus and have to interact with TEADs in nucleus for transcription activation. YAP/TAZ are master transcriptional factors widely activated in human cancers to promote cancer initiation, progression, metastasis and therapy resistance. It has been shown that aberrant YAP/TAZ activation is also associated with the adapted tumor microenvironment (TME) for tumor growth. Dysregulation in Hippo pathway and YAP/TAZ-TEADs transcriptional activity is pervasively associated with various types of cancers, including mesothelioma, squamous cell cancers, liver cancer and lung cancer, making it an attractive target for cancer therapy. Therefore, inhibition of YAP/TAZ oncogenic activity by blocking YAP/TAZ-TEADs interaction is an effective approach for cancer treatment. In this study, we aim to discover small molecule inhibitors that bind to TEADs and disrupt YAP/TAZ-TEADs interaction for cancer therapy. With superposition of all the available crystal structures of four TEAD subtypes in the public database, we found the YAP Ω loop binding site of TEADs is relatively rigid (of backbone atoms), but the side chain flexibility of K289, K265 and V406 in TEAD1 affects the shape of the binding site significantly. Notably, in two TEAD2 structures, e.g. PDB ID: 5dqe and 5dq8, K301 (K274 of TEAD1) adopts an open conformation and accommodates a flufenamic acid to bind in an induced pocket. Using 5dq8 as the protein model, we virtually screened a fragment library, and identified a hit compound that is suitable to combine with flufenamic acid. Interaction between the hit compound and TEAD1 was confirmed by 1D-NMR (STD). Based on the docking poses, we combined the hit and flufenamic acid, designed and synthesized several compounds. Interaction with TEAD1 of the compounds were confirmed by 1D-NMR, SPR and HTRF. Crystal structures of representative compounds confirmed the predicted binding mode in TEAD1. With further medicinal chemistry efforts, we have discovered a series of novel YAP/TAZ-TEAD PPI inhibitors bound at the Ω loop site of TEAD1. Citation Format: Lin Du, Jing Liu, Qinglong Zeng, Ming Xu, Jiting Lu, Qiangang Zheng, Jidong Zhu. Structural dynamics-based hit generation to disrupt YAP/TAZ-TEAD protein-protein interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 326.","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90685484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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