Cancer Chemistry最新文献

{"title":"Abstract LB003: Fragment based discovery of MRTX9768, a synthetic lethal-based inhibitor designed to bind the PRMT5-MTA complex and selectively target MTAP/CDKN2A-deleted tumors","authors":"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","doi":"10.1158/1538-7445.AM2021-LB003","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB003","url":null,"abstract":"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","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76551586","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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}