Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-LB003
Christopher R. Smith, Kulyk Svitlana, J. Lawson, Lars D. Engstrom, Ruth Aranda, David M Briere, Robin J. Gunn, K. Moya, L. Rahbaek, Laurie Waters, A. Ivetac, J. Christensen, P. Olson, M. Marx
The MTAP gene is proximal to and co-deleted in nearly all CDKN2A-deleted cancers. This genetic alteration is present in an estimated 9% of all cancers and is especially prevalent in cancers with high unmet medical need (e.g. mesothelioma (32%), pancreatic (22%), lung squamous (20%)). Multiple independent research teams have demonstrated that tumor cell lines with homozygous MTAP deletions are hypersensitive to shRNA-mediated knock down of PRMT5. MTAP is required for the methionine salvage pathway and MTAP-del cells accumulate MTA, an inhibitory co-factor which competes for binding to the co-factor binding site of PRMT5 with the activating co-factor SAM. PRMT5 is a methyltransferase that adds symmetric dimethylarginine (SDMA) modification to proteins and is essential for mammalian cell survival. A small molecule that selectively binds and stabilizes the catalytically inactive PRMT5•MTA complex may represent a synthetic lethal-based precision medicine for the treatment of MTAP/CDKN2A—del tumors. Notably, 1st generation PRMT5 small molecule inhibitors do not target MTA-complexed PRMT5 and do not exhibit selective inhibition of MTAP-del cancer cells. Here we report a new series of compounds discovered via a fragment-based approach that selectively bind to the PRMT5•MTA complex. A fragment hit was identified in an SPR binding assay with PRMT5•MTA (KD 18 μM). The binding mode was determined by X-ray crystallography and revealed that the fragment makes productive interactions with K333, F327, E435, E444, E435, and W579 of PRMT5 as well as with the co-liganded MTA. Fragment growing aided by structure-based design identified a key interaction with the L312 backbone N-H that enhances binding to PRMT5•MTA (MRTX4646, SPR KD 57 nM). Further exploration highlighted an interaction with the F580 backbone N-H as important for cellular activity and selectivity. This interaction with F580 was illustrated by MRTX7512 which exhibits an IC50 value of 633 nM for inhibition of SDMA in engineered HCT116 MTAP-del cells and demonstrates 15-fold selectivity compared with HCT116 MTAP-WT cells (IC50 9763 nM). Further optimization of cellular potency and pharmacokinetic properties identified MRTX9768, a potent inhibitor of SDMA and cell proliferation in HCT116 MTAP-del cells (SDMA IC50 3 nM; prolif. IC50 11 nM) with marked selectivity over HCT116 MTAP-WT cells (SDMA IC50 544 nM; prolif. IC50 861 nM). In xenograft studies, oral administration of MRTX9768 demonstrates dose-dependent inhibition of SDMA in MTAP-del tumors, with less SDMA modulation observed in bone marrow. In summary, we have used a fragment-based approach to discover a new class of orally active PRMT5•MTA inhibitors that demonstrate selective antitumor activity in MTAP-del tumor cells while sparing MTAP-WT cells. Citation Format: Christopher R. Smith, Svitlana Kulyk, J. D. Lawson, Lars D. Engstrom, Ruth Aranda, David M. Briere, Robin Gunn, Krystal Moya, Lisa Rahbaek, Laura Waters, Anthony Ivetac, James G. Christe
MTAP基因在几乎所有cdkn2a缺失的癌症中都是近端和共缺失的。在所有癌症中，估计有9%存在这种基因改变，在医疗需求未得到满足的癌症中尤其普遍(例如间皮瘤(32%)、胰腺癌(22%)、肺鳞癌(20%))。多个独立研究团队已经证明，MTAP纯合子缺失的肿瘤细胞系对shrna介导的PRMT5敲低敏感。MTAP是甲硫氨酸回收途径所必需的，MTAP-del细胞积累MTA, MTA是一种抑制辅因子，与激活辅因子SAM竞争结合PRMT5的辅因子结合位点。PRMT5是一种甲基转移酶，可将对称二甲基精氨酸(SDMA)修饰添加到蛋白质中，对哺乳动物细胞存活至关重要。一种选择性结合并稳定无催化活性PRMT5•MTA复合物的小分子可能代表了一种基于致命的合成精准药物，用于治疗MTAP/ CDKN2A-del肿瘤。值得注意的是，第一代PRMT5小分子抑制剂不靶向mta络合的PRMT5，也不表现出对MTAP-del癌细胞的选择性抑制。在这里，我们报告了通过基于片段的方法发现的一系列新的化合物，这些化合物选择性地结合到PRMT5•MTA复合物上。在PRMT5•MTA (KD为18 μM)的SPR结合实验中发现了一个片段命中。结合模式通过x射线晶体学确定，发现该片段与PRMT5的K333、F327、E435、E444、E435和W579以及共配的MTA产生了有效的相互作用。在基于结构设计的辅助下，片段生长确定了与L312骨架N-H的关键相互作用，增强了与PRMT5•MTA (MRTX4646, SPR KD 57 nM)的结合。进一步的研究表明，与F580骨架N-H的相互作用对细胞活性和选择性很重要。MRTX7512证实了与F580的相互作用，在HCT116 MTAP-del细胞中抑制SDMA的IC50值为633 nM，与HCT116 MTAP-WT细胞(IC50为9763 nM)相比，其选择性为15倍。进一步优化细胞效度和药代动力学特性，鉴定出HCT116 MTAP-del细胞(SDMA IC50 3 nM;prolif。IC50 11 nM)对HCT116 MTAP-WT细胞有明显的选择性(SDMA IC50 544 nM;prolif。IC50 861 nM)。在异种移植研究中，口服MRTX9768显示出对MTAP-del肿瘤中SDMA的剂量依赖性抑制，在骨髓中观察到较少的SDMA调节。总之，我们使用基于片段的方法发现了一类新的口服活性PRMT5•MTA抑制剂，该抑制剂在MTAP-del肿瘤细胞中表现出选择性抗肿瘤活性，同时保留了MTAP-WT细胞。引用格式:Christopher R. Smith, Svitlana Kulyk, J. D. Lawson, Lars D. Engstrom, Ruth Aranda, David M. Briere, Robin Gunn, crystal Moya, Lisa Rahbaek, Laura Waters, Anthony Ivetac, James G. Christensen, Peter Olson, Matthew A. Marx基于片段的MRTX9768的发现，MRTX9768是一种合成的基于致命的抑制剂，旨在结合PRMT5-MTA复合物并选择性靶向MTAP/ cdkn2a缺失的肿瘤[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nr LB003。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-298
N. Beaton, J. Adhikari, Yuehan Feng, R. Bruderer, R. Tomlinson, I. Cornella-Taracido, L. Reiter
{"title":"Abstract 298: Dissection of drug-protein interactions by HR-LiP-MS in target validation and lead optimization","authors":"N. Beaton, J. Adhikari, Yuehan Feng, R. Bruderer, R. Tomlinson, I. Cornella-Taracido, L. Reiter","doi":"10.1158/1538-7445.AM2021-298","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-298","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77686390","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.AM2021-323
Yu Qian, Jennifer A. Whang, J. Anderl, H. Johnson, C. Kirk, E. Lowe, D. McMinn, Beatriz Millare, T. Muchamuel, Jinhai Wang
{"title":"Abstract 323: Quantitative proteomic profiling of novel anti-cancer small molecule inhibitors of Sec61: Mechanistic investigation and biomarker discovery","authors":"Yu Qian, Jennifer A. Whang, J. Anderl, H. Johnson, C. Kirk, E. Lowe, D. McMinn, Beatriz Millare, T. Muchamuel, Jinhai Wang","doi":"10.1158/1538-7445.AM2021-323","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-323","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"112 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79365156","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.AM2021-311
Federica Giordano, S. Lenna, Riccardo Rampado, A. Ewing, G. Baudo, Matteo Massaro, Assaf Zinger, E. Rosa, J. Yustein, F. Taraballi
Osteosarcoma (OS) is the most common pediatric bone tumor with a worldwide incidence of 3.4 cases per million people annually. Unfortunately, current treatments are still not sufficient to eradicate OS, due to its ability to resist the upfront standard chemotherapy. Therefore, it is essential to identify and effectively deliver novel therapeutic regimens. Multi-tyrosine kinase inhibitors have been explored as new therapeutics for different sarcomas. Among many, Ponatinib (Pon) demonstrated very potent anti-tumor activity, however, it received a black box warning from the FDA due to significant cardiovascular side effects. Recently, our lab developed novel biomimetic nanoparticles (NPs) called Leukosomes (Leuko) capable of encapsulating and effectively releasing Pon. These NPs are synthesized from activated leukocytes, maintaining leukocytes9 tropism towards inflamed endothelium. Leveraging on this technology, we aim to validate the therapeutic potential of Leuko in 3D OS tumor model (sarcospheres) and their ability to target primary murine OS model while concomitantly reducing the detrimental side effects. Given its biological relevance and ability to better recapitulate the tumor structure, a 3D tumor model was chosen to reproduce key properties, such as diffusion limitations and the cellular network of solid tumors that have significant impacts on cancer drug efficacy.In the sarcospheres model, we observed efficient penetration and internalization of NPs in both, murine (RF379, 577) and human PDX derived (PDX94, pPDX202) OS cell lines, where Leuko exhibited a 20% increase in targeting vs the control Liposome (Lipo). This difference was not detected in the control 2D model. Moreover, our data demonstrated a 2-fold increase in the Leuko cytotoxic effect in 3D compared to 2D systems. Murine OS cell viability was 20% lower in sarcospheres after treatment with the IC50 for Pon. In addition, NPs induced complete inhibition of murine sarcosphere formation in the extreme limiting dilution assay (ELDA). These findings were also confirmed using the PDX derived OS cell lines. Subsequently, an in vivo intratibial syngeneic orthotopic mouse model was utilized to determine the targeting and biodistribution of the NPs. Leuko showed an increased targeting and penetration in the tumor 1 and 3h post NPs injection as anticipated by the 3D in vitro studies. By exploiting the inflammatory conditions within the tumor, which increases the Leuko accumulation, these preliminary results advocate the translational potential of this innovative formulation as a new targeted drug delivery approach for OS. This promising platform could improve the clinical therapeutic approaches and lead to improved outcomes and reduced side effects for OS patients. Citation Format: Federica Giordano, Stefania Lenna, Riccardo Rampado, April Ewing, Gherardo Baudo, Matteo Massaro, Assaf Zinger, Enrica De Rosa, Jason T Yustein, Francesca Taraballi. Ponatinib loaded leukocyte-based nanoparticles
骨肉瘤(Osteosarcoma, OS)是最常见的儿童骨肿瘤，全世界每年的发病率为每百万人3.4例。不幸的是，目前的治疗仍然不足以根除OS，因为它能够抵抗前期的标准化疗。因此，确定并有效地提供新的治疗方案至关重要。多种酪氨酸激酶抑制剂已被探索作为不同肉瘤的新疗法。在许多药物中，Ponatinib (Pon)显示出非常有效的抗肿瘤活性，然而，由于显着的心血管副作用，它收到了FDA的黑框警告。最近，我们的实验室开发了一种新型仿生纳米粒子(NPs)，称为白细胞(Leuko)，能够封装并有效释放Pon。这些NPs由活化的白细胞合成，维持白细胞对炎症内皮的趋向性。利用这一技术，我们的目标是验证白血病在3D OS肿瘤模型(肌球)中的治疗潜力，以及它们靶向原发性小鼠OS模型的能力，同时减少有害的副作用。考虑到其生物学相关性和更好地概括肿瘤结构的能力，我们选择了3D肿瘤模型来再现对癌症药物疗效有重大影响的实体肿瘤的扩散限制和细胞网络等关键特性。在肌球模型中，我们观察到NPs在小鼠(RF379, 577)和人PDX衍生的(PDX94, pPDX202) OS细胞系中的有效渗透和内化，其中白细胞的靶向性比对照脂质体(Lipo)增加了20%。在对照2D模型中没有检测到这种差异。此外，我们的数据表明，与2D系统相比，3D系统的白细胞毒性效应增加了2倍。用IC50治疗Pon后，小鼠肌球中OS细胞活力降低20%。此外，在极限稀释试验(ELDA)中，NPs诱导小鼠肌球形成完全抑制。这些发现也在PDX衍生的OS细胞系中得到证实。随后，利用体内胫骨内同源原位小鼠模型来确定NPs的靶向性和生物分布。白细胞在NPs注射1和3小时后显示出增加的靶向性和穿透性，正如3D体外研究所预测的那样。通过利用肿瘤内的炎症条件，增加白细胞的积累，这些初步结果倡导这种创新配方作为一种新的靶向给药方法的转化潜力。这个有希望的平台可以改善临床治疗方法，改善OS患者的预后并减少副作用。引文格式:Federica Giordano, Stefania Lenna, Riccardo Rampado, April Ewing, Gherardo Baudo, Matteo Massaro, Assaf Zinger, Enrica De Rosa, Jason T Yustein, Francesca Taraballi。波纳替尼负载的白细胞纳米颗粒用于骨肉瘤肌球肿瘤模型的治疗[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311期。
{"title":"Abstract 311: Ponatinib loaded leukocyte-based nanoparticles for osteosarcoma treatment in sarcosphere tumor model","authors":"Federica Giordano, S. Lenna, Riccardo Rampado, A. Ewing, G. Baudo, Matteo Massaro, Assaf Zinger, E. Rosa, J. Yustein, F. Taraballi","doi":"10.1158/1538-7445.AM2021-311","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-311","url":null,"abstract":"Osteosarcoma (OS) is the most common pediatric bone tumor with a worldwide incidence of 3.4 cases per million people annually. Unfortunately, current treatments are still not sufficient to eradicate OS, due to its ability to resist the upfront standard chemotherapy. Therefore, it is essential to identify and effectively deliver novel therapeutic regimens. Multi-tyrosine kinase inhibitors have been explored as new therapeutics for different sarcomas. Among many, Ponatinib (Pon) demonstrated very potent anti-tumor activity, however, it received a black box warning from the FDA due to significant cardiovascular side effects. Recently, our lab developed novel biomimetic nanoparticles (NPs) called Leukosomes (Leuko) capable of encapsulating and effectively releasing Pon. These NPs are synthesized from activated leukocytes, maintaining leukocytes9 tropism towards inflamed endothelium. Leveraging on this technology, we aim to validate the therapeutic potential of Leuko in 3D OS tumor model (sarcospheres) and their ability to target primary murine OS model while concomitantly reducing the detrimental side effects. Given its biological relevance and ability to better recapitulate the tumor structure, a 3D tumor model was chosen to reproduce key properties, such as diffusion limitations and the cellular network of solid tumors that have significant impacts on cancer drug efficacy.In the sarcospheres model, we observed efficient penetration and internalization of NPs in both, murine (RF379, 577) and human PDX derived (PDX94, pPDX202) OS cell lines, where Leuko exhibited a 20% increase in targeting vs the control Liposome (Lipo). This difference was not detected in the control 2D model. Moreover, our data demonstrated a 2-fold increase in the Leuko cytotoxic effect in 3D compared to 2D systems. Murine OS cell viability was 20% lower in sarcospheres after treatment with the IC50 for Pon. In addition, NPs induced complete inhibition of murine sarcosphere formation in the extreme limiting dilution assay (ELDA). These findings were also confirmed using the PDX derived OS cell lines. Subsequently, an in vivo intratibial syngeneic orthotopic mouse model was utilized to determine the targeting and biodistribution of the NPs. Leuko showed an increased targeting and penetration in the tumor 1 and 3h post NPs injection as anticipated by the 3D in vitro studies. By exploiting the inflammatory conditions within the tumor, which increases the Leuko accumulation, these preliminary results advocate the translational potential of this innovative formulation as a new targeted drug delivery approach for OS. This promising platform could improve the clinical therapeutic approaches and lead to improved outcomes and reduced side effects for OS patients. Citation Format: Federica Giordano, Stefania Lenna, Riccardo Rampado, April Ewing, Gherardo Baudo, Matteo Massaro, Assaf Zinger, Enrica De Rosa, Jason T Yustein, Francesca Taraballi. Ponatinib loaded leukocyte-based nanoparticles","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":"85922473","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.AM2021-18
M. Anurag, Eric J. Jaehnig, S. Satpathy, Karsten Krug, Jonathan T. Lei, Yongchao Dou, Beom-Jun Kim, C. Sullivan, D. Mani, Erik J. Bergstrom, G. Echeverria, I. Hagemann, Kristen Otte, Henry Rodriguez, A. Robles, M. Lewis, Michael A. Gillette, Bing Zhang, M. Rimawi, S. Carr, F. Ademuyiwa, M. Ellis
{"title":"Abstract 18: Molecular dissection of chemotherapy response in triple negative breast cancer (TNBC) using microscaled proteogenomics","authors":"M. Anurag, Eric J. Jaehnig, S. Satpathy, Karsten Krug, Jonathan T. Lei, Yongchao Dou, Beom-Jun Kim, C. Sullivan, D. Mani, Erik J. Bergstrom, G. Echeverria, I. Hagemann, Kristen Otte, Henry Rodriguez, A. Robles, M. Lewis, Michael A. Gillette, Bing Zhang, M. Rimawi, S. Carr, F. Ademuyiwa, M. Ellis","doi":"10.1158/1538-7445.AM2021-18","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-18","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82744582","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.AM2021-327
Tzu-Chun Chen, Katelyn M Larkin, S. Dames, Hsiao-Yun Huang, Kevin Lai, Jessica Sheu, Timothy H Barnes, Katia Star, Manqing Hong, Bosun Min, Ryan T. Demeter, Ashley Dvorak, Ushati Das Chakravarty, Patrick J. Lau, S. Henck
{"title":"Abstract 327: High conversion library preparation with optimal hybridization capture panel design strategy in RNA-seq","authors":"Tzu-Chun Chen, Katelyn M Larkin, S. Dames, Hsiao-Yun Huang, Kevin Lai, Jessica Sheu, Timothy H Barnes, Katia Star, Manqing Hong, Bosun Min, Ryan T. Demeter, Ashley Dvorak, Ushati Das Chakravarty, Patrick J. Lau, S. Henck","doi":"10.1158/1538-7445.AM2021-327","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-327","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82634301","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.AM2021-300
D. Debnath, R. Petty, N. Sabnis, Jinmin Zhang, A. Lacko, H. Souza, P. F. Filho, J. Mathis, R. Fudała
Based on data from the World Health Organization, breast cancer is the most common type of cancer among women, accounting for about 15% of all cancer-related deaths. Thus, new treatment options are urgently needed to decrease this mortality rate. In recent years, mesoionic compounds have shown promising potential as anti-cancer agents due to their unique structure and reaction properties. We recently reported that a 1,3-thiazolium-5-thiolate mesoionic compound (MIH 2.4Bl) inhibited oxidative phosphorylation in the MCF-7 breast cancer cell line compared to normal human mammary epithelial cells. Furthermore, MIH 2.4Bl induced cytotoxicity by activating autography-related proteins (Beclin-1 and ATG5) and cell cycle arrest at the G2/M phase. Based on our previous findings, MIH 2.4BI is a promising candidate for treating breast cancer. However, a major challenge facing cancer therapeutics is tumor delivery in vivo for the selective destruction of malignant cells while sparing normal cells to preserve tissue integrity. The development and use of drug delivery systems is a recognized approach to improve the efficacy of chemotherapy agents. Nonetheless, drug delivery systems have been largely unexplored in the context of mesoionic compounds. Lipoproteins are ideal for carrying transporting lipophilic anti-cancer drugs and imaging agents as they circulate in the bloodstream for an extended period. In addition, the hydrophobic core of lipoprotein particles allows the incorporation of lipophilic components (including a number of anti-cancer agents). Reconstituted high-density lipoprotein (rHDL) mimics the structure and function of endogenous (i.e., human plasma) HDL and thus presents a potentially markedly improved therapeutic strategy for cancer drug delivery. Previous studies from our group have shown that a stable reconstituted synthetic rHDL-drug complex could be prepared by combining paclitaxel and other chemotherapy drugs using the natural lipid and protein components of circulating HDL via a novel procedure. In this preliminary work, we present an improved strategy of using a newly developed formulation of MIH 2.4BI compound with rHDL nanoparticles as the delivery agent. Also, physico-chemical characterization of the nanoparticles and cytotoxicity analyses using a panel of breast cancer cell lines were performed. These studies support the potential therapeutic use of MIH 2.4Bl in treating breast cancer. (D. Debnath and R.M. Petty contributed equally to this work) Citation Format: Dipti Debnath, R. Max Petty, Nirupama Sabnis, Jinmin Zhang, Andras G. Lacko, Helivaldo Diogenes Souza, Petronio Filgueiras Filho, J. Michael Mathis, Rafal Fudala. An improved strategy for delivering the mesoionic compound MIH 2.4Bl utilizing reconstituted high density nanoparticles (rHDL) in treating breast 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
根据世界卫生组织的数据，乳腺癌是女性中最常见的癌症类型，约占所有癌症相关死亡人数的15%。因此，迫切需要新的治疗方案来降低这一死亡率。近年来，介离子化合物由于其独特的结构和反应性质，在抗癌方面显示出很大的潜力。我们最近报道了一种1,3-噻唑-5-硫酸盐介离子化合物(MIH 2.4Bl)在MCF-7乳腺癌细胞系中抑制氧化磷酸化，与正常人乳腺上皮细胞相比。此外，MIH 2.4Bl通过激活签名相关蛋白(Beclin-1和ATG5)和细胞周期阻滞在G2/M期诱导细胞毒性。根据我们之前的研究结果，MIH 2.4BI是治疗乳腺癌的有希望的候选药物。然而，癌症治疗面临的一个主要挑战是肿瘤的体内递送，以选择性地破坏恶性细胞，同时保留正常细胞以保持组织的完整性。开发和使用给药系统是公认的提高化疗药物疗效的方法。尽管如此，在介离子化合物的背景下，药物输送系统在很大程度上尚未被探索。脂蛋白是理想的运输亲脂性抗癌药物和显像剂，因为它们在血液中循环了很长一段时间。此外，脂蛋白颗粒的疏水核心允许掺入亲脂成分(包括一些抗癌剂)。重组高密度脂蛋白(rHDL)模仿内源性(即人血浆)高密度脂蛋白的结构和功能，因此提出了一种潜在的显著改善癌症药物输送的治疗策略。我们小组先前的研究表明，通过一种新的方法，利用循环HDL的天然脂质和蛋白质成分，将紫杉醇和其他化疗药物结合，可以制备稳定的合成rhdl -药物复合物。在这项初步工作中，我们提出了一种改进的策略，使用新开发的以rHDL纳米颗粒作为递送剂的MIH 2.4BI化合物配方。此外，纳米颗粒的物理化学特性和细胞毒性分析使用一组乳腺癌细胞系进行。这些研究支持MIH 2.4Bl在治疗乳腺癌中的潜在治疗用途。(D. Debnath和R.M. Petty对本文贡献相同)引文格式:Dipti Debnath, R. Max Petty, Nirupama Sabnis, Jinmin Zhang, Andras G. Lacko, Helivaldo Diogenes Souza, Petronio Filgueiras Filho, J. Michael Mathis, Rafal Fudala。利用重组高密度纳米颗粒(rHDL)递送介离子化合物MIH 2.4Bl治疗乳腺癌的改进策略[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300期。
{"title":"Abstract 300: An improved strategy for delivering the mesoionic compound MIH 2.4Bl utilizing reconstituted high density nanoparticles (rHDL) in treating breast cancer","authors":"D. Debnath, R. Petty, N. Sabnis, Jinmin Zhang, A. Lacko, H. Souza, P. F. Filho, J. Mathis, R. Fudała","doi":"10.1158/1538-7445.AM2021-300","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-300","url":null,"abstract":"Based on data from the World Health Organization, breast cancer is the most common type of cancer among women, accounting for about 15% of all cancer-related deaths. Thus, new treatment options are urgently needed to decrease this mortality rate. In recent years, mesoionic compounds have shown promising potential as anti-cancer agents due to their unique structure and reaction properties. We recently reported that a 1,3-thiazolium-5-thiolate mesoionic compound (MIH 2.4Bl) inhibited oxidative phosphorylation in the MCF-7 breast cancer cell line compared to normal human mammary epithelial cells. Furthermore, MIH 2.4Bl induced cytotoxicity by activating autography-related proteins (Beclin-1 and ATG5) and cell cycle arrest at the G2/M phase. Based on our previous findings, MIH 2.4BI is a promising candidate for treating breast cancer. However, a major challenge facing cancer therapeutics is tumor delivery in vivo for the selective destruction of malignant cells while sparing normal cells to preserve tissue integrity. The development and use of drug delivery systems is a recognized approach to improve the efficacy of chemotherapy agents. Nonetheless, drug delivery systems have been largely unexplored in the context of mesoionic compounds. Lipoproteins are ideal for carrying transporting lipophilic anti-cancer drugs and imaging agents as they circulate in the bloodstream for an extended period. In addition, the hydrophobic core of lipoprotein particles allows the incorporation of lipophilic components (including a number of anti-cancer agents). Reconstituted high-density lipoprotein (rHDL) mimics the structure and function of endogenous (i.e., human plasma) HDL and thus presents a potentially markedly improved therapeutic strategy for cancer drug delivery. Previous studies from our group have shown that a stable reconstituted synthetic rHDL-drug complex could be prepared by combining paclitaxel and other chemotherapy drugs using the natural lipid and protein components of circulating HDL via a novel procedure. In this preliminary work, we present an improved strategy of using a newly developed formulation of MIH 2.4BI compound with rHDL nanoparticles as the delivery agent. Also, physico-chemical characterization of the nanoparticles and cytotoxicity analyses using a panel of breast cancer cell lines were performed. These studies support the potential therapeutic use of MIH 2.4Bl in treating breast cancer. (D. Debnath and R.M. Petty contributed equally to this work) Citation Format: Dipti Debnath, R. Max Petty, Nirupama Sabnis, Jinmin Zhang, Andras G. Lacko, Helivaldo Diogenes Souza, Petronio Filgueiras Filho, J. Michael Mathis, Rafal Fudala. An improved strategy for delivering the mesoionic compound MIH 2.4Bl utilizing reconstituted high density nanoparticles (rHDL) in treating breast 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 ","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87198066","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.AM2021-275
Christoph Bauer, M. Quante, Carla Regina, Michaela Schneider, G. Andrieux, O. Gorka, O. Gross, M. Boerries, B. Kammerer, S. Hettmer
{"title":"Abstract 275: Lack of electron acceptors contributes to redox stress and growth arrest in asparagine-starved sarcoma cells","authors":"Christoph Bauer, M. Quante, Carla Regina, Michaela Schneider, G. Andrieux, O. Gorka, O. Gross, M. Boerries, B. Kammerer, S. Hettmer","doi":"10.1158/1538-7445.AM2021-275","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-275","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74350571","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.AM2021-295
D. Thomas, Tom A. Fleming, M. Bittner
About 50 kinase inhibitors have been approved by the FDA for different indications so far. On the way from target validation to approval, the biochemical characterisation of a novel kinase inhibitor is a challenging, yet absolutely critical task. High resolution, kinetic molecular profiling can enable better data-driven decision making early on in the drug discovery process, not only saving time and resources, but also leading to superior molecular design. Arctoris developed a robotics-enabled process for fully automated kinase inhibitor characterisation, providing an unparalleled depth of data capture, going beyond the current state-of-the-art of biochemical assay setup. We validated our technology platform establishing assays against four members of the Janus Kinase family (JAK1, JAK2, JAK3, TYK2), profiling a set of JAK inhibitors. Of note, several JAK inhibitors with prior FDA approval for other indications entered clinical trials for COVID-19 treatment, making this target class particularly relevant for an in-depth study. Reagent validation, assay development, calibration, and optimization were expedited through systematic multifactorial experimental design, high density assay plate formats and versatile automated liquid handling. The Arctoris Ulysses platform affords 9 orders of magnitude range in liquid volume handling, with picolitre precision and contact-free digital dispensing for true, non-serial, independent experimentation. Fully automated protocols were optimized, validated, versioned, and explicitly encoded. Robust potency measurements of all inhibitors were established against each of the JAK targets, revealing molecules with distinct isoform selectivity. Designing and selecting molecules with specific activity profiles enables the fine tuning of pharmacology and the avoidance of unwanted off-target toxicity. Our unique platform, assay design, and deep expertise enabled the identification of molecules within the JAK inhibitor set that exhibit a range of kinetic properties. Our mechanistic analyses can help to elucidate the mode of inhibition (competitive, allosteric, synergistic etc.) as well as provide information pertaining to the kinetic selectivity that may be present but missed by focusing solely on potency.
{"title":"Abstract 295: Implementing fully automated kinase inhibitor characterization using a robotic system","authors":"D. Thomas, Tom A. Fleming, M. Bittner","doi":"10.1158/1538-7445.AM2021-295","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-295","url":null,"abstract":"About 50 kinase inhibitors have been approved by the FDA for different indications so far. On the way from target validation to approval, the biochemical characterisation of a novel kinase inhibitor is a challenging, yet absolutely critical task. High resolution, kinetic molecular profiling can enable better data-driven decision making early on in the drug discovery process, not only saving time and resources, but also leading to superior molecular design. Arctoris developed a robotics-enabled process for fully automated kinase inhibitor characterisation, providing an unparalleled depth of data capture, going beyond the current state-of-the-art of biochemical assay setup. We validated our technology platform establishing assays against four members of the Janus Kinase family (JAK1, JAK2, JAK3, TYK2), profiling a set of JAK inhibitors. Of note, several JAK inhibitors with prior FDA approval for other indications entered clinical trials for COVID-19 treatment, making this target class particularly relevant for an in-depth study. Reagent validation, assay development, calibration, and optimization were expedited through systematic multifactorial experimental design, high density assay plate formats and versatile automated liquid handling. The Arctoris Ulysses platform affords 9 orders of magnitude range in liquid volume handling, with picolitre precision and contact-free digital dispensing for true, non-serial, independent experimentation. Fully automated protocols were optimized, validated, versioned, and explicitly encoded. Robust potency measurements of all inhibitors were established against each of the JAK targets, revealing molecules with distinct isoform selectivity. Designing and selecting molecules with specific activity profiles enables the fine tuning of pharmacology and the avoidance of unwanted off-target toxicity. Our unique platform, assay design, and deep expertise enabled the identification of molecules within the JAK inhibitor set that exhibit a range of kinetic properties. Our mechanistic analyses can help to elucidate the mode of inhibition (competitive, allosteric, synergistic etc.) as well as provide information pertaining to the kinetic selectivity that may be present but missed by focusing solely on potency.","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89277580","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.AM2021-314
W. P. D. W. Thilakarathna, H. Rupasinghe
{"title":"Abstract 314: Highly polymeric grape seed proanthocyanidins: A call for establishing the safe dose","authors":"W. P. D. W. Thilakarathna, H. Rupasinghe","doi":"10.1158/1538-7445.AM2021-314","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-314","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83600541","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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