bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3849: Structure-based PROTAC design demonstrates BAF complex ATPase vulnerabilities in cancer
Authors: Koegl Manfred , Farnaby William , Whitworth Claire , Roy Michael , Diers Emelyne , Trainor Nicole , Steurer Steffen , Riedmueller Carina , Gmaschitz Teresa , Wachter Johannes , Dank Christian , Gallant Michael , Sharps Bernadette , Rumpel Klaus , Traxler Elisabeth , Lorenz Romario , Petermann Oliver , Greb Peter , Weinstabl Harald , Bader Gerd , Zoephel Andreas , Weiss-Puxbaum Alexander , Rinnenthal Joerg , Arnnhof Heribert , Wiechens Nicola , Wu Meng-Ying , Owen-Hughes Tom , Ettmayer Peter , Pearson Mark , McConnell Darryl B. , Ciulli Alessio 
Published: August 2019

Abstract
Targeting subunits of BAF/PBAF complexes has been proposed as an approach to exploit cancer vulnerabilities, yet small molecules developed to date have remained largely ineffectual. Here we develop PROTAC degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided the rational optimization of ACBI1, a potent cooperative SMARCA2/4 degrader. ACBI1 induced antiproliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics and structure driven campaign to degrade targets previously considered undruggable, and pave the way towards new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.
Citation Format: Manfred Koegl, William Farnaby, Claire Whitworth, Michael Roy, Emelyne Diers, Nicole Trainor, Steffen Steurer, Carina Riedmueller, Teresa Gmaschitz, Johannes Wachter, Christian Dank, Michael Gallant, Bernadette Sharps, Klaus Rumpel, Elisabeth Traxler, Romario Lorenz, Oliver Petermann, Peter Greb, Harald Weinstabl, Gerd Bader, Andreas Zoephel, Alexander Weiss-Puxbaum, Joerg Rinnenthal, Heribert Arnnhof, Nicola Wiechens, Meng-Ying Wu, Tom Owen-Hughes, Peter Ettmayer, Mark Pearson, Darryl B. McConnell, Alessio Ciulli. Structure-based PROTAC design demonstrates BAF complex ATPase vulnerabilities in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3849.
Abstract 3851: An Aurora kinase inhibitor BPR6K471 inhibits tumor growth and reduces the cancer stem cell-like properties of small cell lung cancer
Authors: Chang Chun-Ping , Ke Yi-Yu , Lin Wen-Hsing , Jhuo Dai-Hui , Wang Wan-Ping , Tsai Chia-Hua , Chen Yen-Ting , Su Yu-Jie , Hung Ming-Chun , Wu Zhong-Wei , Kuo Po-Chu , Yeh Teng-Kuang , Chen Ching-Ping , Song Jen-Shin , Chen Chiun-Tong , Shih Chuan , Chi Ya-Hui 
Published: August 2019

Abstract
Small cell lung cancer (SCLC) is one the most aggressive tumors with poor survival rate. SCLC patients often present with metastasis at time of diagnosis, excluding surgery as a treatment option. While patients show high response rate to standard chemotherapy such as cisplatin/etoposide, they soon develop drug resistance and disease progression. Therefore, new therapeutic strategies are urgently needed for SCLC. Several characteristics of SCLC such as aggressiveness and drug resistance could attribute to the existence of a cancer stem cell (CSC) subpopulation in SCLC. The SCLC cell line NCI-H446 has been shown to present high degree of stemness and express stem cell markers including CD133, OCT4, MYC and Nestin. Here we develop a pyrimidine-based small molecule BPR6K471 which potently inhibits Aurora kinase activities in enzymatic- and cell- based assays. BPR6K471 efficiently (IC50 = 66 nM) inhibits proliferation of NCI-H446, and reduces the expression of stem-cell markers. In addition, intravenous injection of BPR6K471 inhibits &gt;90 % progression of NCI-H446 in a mouse xenograft model. These results suggest that targeting Aurora kinases may be a potential therapeutic strategy to combat the CSC subpopulation in SCLC.
Citation Format: Chun-Ping Chang, Yi-Yu Ke, Wen-Hsing Lin, Dai-Hui Jhuo, Wan-Ping Wang, Chia-Hua Tsai, Yen-Ting Chen, Yu-Jie Su, Ming-Chun Hung, Zhong-Wei Wu, Po-Chu Kuo, Teng-Kuang Yeh, Ching-Ping Chen, Jen-Shin Song, Chiun-Tong Chen, Chuan Shih, Ya-Hui Chi. An Aurora kinase inhibitor BPR6K471 inhibits tumor growth and reduces the cancer stem cell-like properties of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3851.
Abstract 3858: Inflammation and oncogene in hepatocellular carcinoma: Clinical relevance and experimental targeted therapy
Authors: Wang Wei , Cheng Jianwen , Qin Jiang-Jiang , Hu Bo , Nijampatnam Bhavitavya , Velu Sadanandan , Yang Xin-Rong , Fan Jia , Zhang Ruiwen 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) poses a major public health problem worldwide and novel, effective therapeutic approaches for this devastating disease are urgently needed. The overexpression or activation of the MDM2 oncogene frequently occurs in HCC and is linked to cancer growth, poor survival, metastasis, and resistance to treatment. We have hypothesized that MDM2 is a promising therapeutic target for HCC therapy. We have recently discovered that the transcription factor NFAT1 upregulates MDM2 expression, promoting cancer cell growth, migration, invasion, and angiogenesis. The present study was designed to demonstrate the role of the NFAT1-MDM2 pathway in HCC progression and its value in developing HCC targeted therapy. We systemically investigated the expression and association of MDM2 and NFAT1 in 254 pairs of human HCC and matched non-cancerous tissue samples. High-throughput virtual and cell-based screenings were carried out for search for lead compounds targeting both NFAT1 and MDM2. The in vitro and in vivo anti-HCC activities and underlying mechanisms of action were further evaluated in HCC cell lines with various p53 backgrounds. Our results demonstrated that, compared with the non-malignant peritumoral tissues MDM2 and NFAT1 were overexpressed in HCC tissues, which were correlated with poor prognosis and increased metastasis. Based on molecular modeling study, Biacore assay, and pull-down assays, one of the lead compounds, named MA242, was identified as a potent and selective MDM2 and NFAT1 dual inhibitor. Mechanistically, M242 directly bound to MDM2 and NFAT1 proteins with high affinity and induced their protein degradation. MA242 also inhibited NFAT1-mediated MDM2 transcription. At cellular level, MA242 decreased cell proliferation, and induced apoptosis and G2/M phase arrest in various HCC cell lines, regardless of the p53 status. Furthermore, M242 inhibited the tumor growth and metastasis in orthotopic and patient-derived xenograft (PDX) models of HCC, without any obvious host toxicity. In conclusion, MDM2 and NFAT1 expression can serve as predictors of survival in patients with HCC. Dual MDM2 and NFAT1 inhibitors may represent a first-in-class clinical candidates for the treatment of HCC, including tumors lacking functional p53. This project is supported by NIH R01 CA186662 and R01 CA214019 and ACS RSG-15-009-01-CDD.
Citation Format: Wei Wang, Jianwen Cheng, Jiang-Jiang Qin, Bo Hu, Bhavitavya Nijampatnam, Sadanandan Velu, Xin-Rong Yang, Jia Fan, Ruiwen Zhang. Inflammation and oncogene in hepatocellular carcinoma: Clinical relevance and experimental targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3858.
Abstract 3859: Targeting CDK9 and MCL-1 by a New CDK9/p-TEFB Inhibitor with and without 5-fluorouracil in esophageal adenocarcinoma
Authors: Tong zhimin , Mejia Alicia , Veeranki Omkara , Verma Anuj , Correa Arlene , Patel Viren , Dokey Rashmi , Solis Luisa , Mino Barbara , Kathkuda Riham , Canales Jaime , Lin Steven , Krishnan Sunil , Kopetz Scott , Blum Mariela , Ajani Jaffer , Hofstetter Wayne , Maru Dipen M 
Published: August 2019

Abstract
Background: CDK9 inhibitors are anti-tumorigenic against several solid tumors including esophageal adenocarcinoma (EAC). However, efficacy of CDK9 inhibitor as adjuvant to chemotherapy and target proteins shared between these two drugs are not known.
Methods: Efficacy of a new CDK9 inhibitor, BAY1143572 with and without 5-fluorouracil (5-FU) on tumor growth was tested in vitro and xenograft models of EAC. We tested effects of these agents on MCL-1 in vitro. We also analyzed a possible role of MCL-1 as a predictor of survival in patients with EAC.
Results: BAY1143572 had a dose-dependent anti-proliferative and pro-apoptotic effects in vitro. BAY1143572 and 5-FU had strong synergy in vitro. Median tumor volume of FLO1 or ESO26 xenografts in cohort treated with combination of two drugs was 82% or 55% smaller than the cohort treated with 5-FU alone, and 46 % or 33% smaller than the cohort treated with BAY114352 alone (p&lt;0.05). BAY1143572 transcriptionally downregulated MCL-1 by inhibiting HIF-1α binding to the MCL-1 promoter. 5-FU enhanced BAY1143572 induced MCL-1 downregulation in vitro. Stable overexpression of MCL-1 reduced apoptosis by BAY1143572 and 5-FU. Higher tumor cell MCL-1 expression correlated with shorter overall survival in patients with EAC treated with chemoradiation and surgery.
Conclusion: CDK9 inhibitor and 5-FU are synergistic and MCL-1 is a target of CDK9 inhibitor in EAC.
Citation Format: zhimin Tong, Alicia Mejia, Omkara Veeranki, Anuj Verma, Arlene Correa, Viren Patel, Rashmi Dokey, Luisa Solis, Barbara Mino, Riham Kathkuda, Jaime Canales, Steven Lin, Sunil Krishnan, Scott Kopetz, Mariela Blum, Jaffer Ajani, Wayne Hofstetter, Dipen M Maru. Targeting CDK9 and MCL-1 by a New CDK9/p-TEFB Inhibitor with and without 5-fluorouracil in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3859.
Abstract 3863: Specifically targeting PDIA1 with indene inhibitors leads to bortezomib-potentiation in multiple myeloma
Authors: Robinson Reeder M. , Reyes Leticia , Duncan Ravyn , Dolloff Nathan 
Published: August 2019

Abstract
Protein disulfide isomerase (PDI) is an emerging therapeutic target in oncology. PDI inhibitors have demonstrated a unique propensity to overcome resistance to existing cancer therapies, although drug candidates have not yet progressed to the stage of clinical development. We recently reported the discovery of lead indene compound E64FC26 as a potent pan-PDI inhibitor that enhances the cytotoxic effects of proteasome inhibitors (PIs) in panels of Multiple Myeloma (MM) cells and MM mouse models [1]. An extensive medicinal chemistry program has led to the generation of a diverse library of indene-containing molecules with varying degrees of PI-potentiating activity. The results show detailed structure activity relationships (SAR) with a high degree of correlation between potency of PDIA1 inhibition and bortezomib (Btz) potentiation in MM cells. Inhibition of PDIA1 in MM leads to ER and oxidative stress characterized by the accumulation of misfolded poly-ubiquitinated proteins and the induction of UPR biomarkers ATF4, CHOP, and Nrf2. Furthermore, an advanced derivative, E64FC65, was identified as a PDIA1 selective inhibitor as it was significantly weaker against PDIA3, PDIA4, TXNDC5, PDIA6, and thioredoxin when compared to E64FC26 (Table 1). We purified the redox-active a and a’ thioredoxin-like domains of PDI and found that E64FC65 only inhibited the a domain while E64FC26 inhibited both a and a’ domains. The PDI isoform and domain selectivity of E64FC65 imparted increased anti-cancer activity while reducing toxicity against primary activated human T-cells. Additionally, E64FC65 exhibited improved pharmaceutical properties in ADME assays. This work shows the generation of a PDIA1 a domain specific indene inhibitor that potentiates Btz cytotoxicity in MM cells while abrogating toxicity in normal cells. E64FC65 is thus a favorable PDI inhibitor candidate for further development.
Citation Format: Reeder M. Robinson, Leticia Reyes, Ravyn Duncan, Nathan Dolloff. Specifically targeting PDIA1 with indene inhibitors leads to bortezomib-potentiation in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3863.
Abstract 3881: Relating tumor drug concentrations to target effect with semi physiologic PK-PD modeling in drug development: An application using a novel dCK inhibitor
Authors: Poddar Soumya , Nikanjam Mina , Capparelli Edmund , Le Thuc , Wei Liu , Radu Caius 
Published: August 2019

Abstract
Introduction: Deoxycytidine kinase (dCK) is essential for DNA synthesis through salvage pathways and DI-87 is a novel dCK inhibitor in preclinical development. This study used PET imaging to measure dCK inhibition and pharmacokinetic-pharmacodynamic (PK-PD) modeling to relate tumor drug levels to tissue with dCK activity and tumor shrinkage.
Methods: Oral DI-87 was administered to NSG mice with plasma and tumor PK assessed over 24 hrs by mass spectrometry. NSG mice with CEM tumors were administered varying doses of DI-87 followed by the [18F]CFA PET probe and PET imaging. NSG mice with CEM tumors were administered thymidine and DI-87 concurrently and tumor growth monitored. PK-PD modeling was conducted with NONMEM (v. 7.3).
Results: DI-87 plasma concentrations peaked at 3 hr; tumor peak concentrations occurred later. Tumor concentrations were less than one third of plasma concentrations. Full dCK inhibition by PET imaging occurred between 10 and 25 mg/kg and decreasing doses led to faster recovery of activity. Full recovery of enzyme activity occurred by 36 hrs with full inhibition being maintained at the 12 hr time point at the 25 mg/kg dose. Maximal growth inhibition occurred with full dCK inhibition over the dosing range (25 mg/kg BID) when DI-87 was given in combination therapy with thymidine; thus increased doses led to more persistent dCK inhibition with predictable increased growth inhibition.
Conclusions: Combining PET probes with PK-PD modeling led to an optimized dosing schedule for combination therapy with DI-87.
Citation Format: Soumya Poddar, Mina Nikanjam, Edmund Capparelli, Thuc Le, Liu Wei, Caius Radu. Relating tumor drug concentrations to target effect with semi physiologic PK-PD modeling in drug development: An application using a novel dCK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3881.
Abstract 391: Serine/threonine kinase LASK2 as a biomarker and therapeutic target for lung cancer
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke 
Published: August 2019

Abstract
Since the number of lung cancer patients responding well to standard chemotherapies is still small, further development of new anti-cancer drugs with minimum risk of adverse effects and highly sensitive cancer biomarkers for precision medicine is eagerly required. We have been developing new molecular therapies targeting oncogenic proteins with their companion diagnostics by screening system as follows; i) To identify overexpressed genes in 120 lung cancers by our original gene expression profile database, ii) To confirm the candidate genes for their low expression in 23 normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering hundreds of non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the growth/invasion of cancer cells by siRNAs. During this process, we selected dozens of druggable oncoproteins with various enzymatic activities, and detected higher expression of serine/threonine kinase LASK2 (lung cancer-associated kinase 2) in the majority of various types of lung cancers, but scarce expression in normal tissues except testis. We further observed much higher expression patterns of LASK2 in brain metastasis as well as advanced primary lung tumors, compared to those in earlier-stage primary lung tumors. Immunohistochemical analysis using tissue microarray showed that strong LASK2 positivity was an independent prognostic factor for NSCLC (P&lt;0.0001). Suppression of LASK2 expression with its siRNAs inhibited growth of lung cancer cells, whereas enhanced cellular proliferation by exogenous expression of LASK2 in mammalian cells also supported its oncogenic function in vitro and in mice model. Invasion of mammalian cells transfected with LASK2-expression vector through Matrigel was significantly enhanced, compared to the control cells transfected with mock or LASK2-kinase dead vector, suggesting that LASK2 could also contribute to the highly malignant phenotype of lung-cancer cells. Induction of LASK2 appeared to activate oncogenic signals for lung cancer such as phosphorylation of MAPK and PCNA. Our data indicate that LASK2 is a promising diagnostic biomarker and therapeutic target for developing precision medicine of lung cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Serine/threonine kinase LASK2 as a biomarker and therapeutic target for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 391.
Abstract 3911: Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression
Authors: Wu Yi-Hui , Chou Cheng-Yang 
Published: August 2019

Abstract
Background and aims: Akt plays a central role in regulating cell growth and cell cycle progression and is regarded as a promising therapeutic target. We examined whether Akt inhibition by SC66 is therapeutically efficacious in the treatment of ovarian cancer as a single agent and in combination with chemotherapy drugs.
Methods: The expressions of phospho-Akt in ovarian cancer patients were evaluated by immunohistochemistry. Using eight human ovarian cancer cell lines, we determined the effect of SC66 by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, western blot, and apoptosis assays. We evaluated the association between phospho-Akt/mTOR, COL11A1 and SC66 sensitivity. We also determined the effect of SC66 on tumor growth using mice inoculated with human ovarian cancer cells.
Results: Elevated phospho-Akt levels in cancerous tissue were associated with short progression-free survival and overall survival. Cell sensitivity to SC66 was inversely correlated with phospho-Akt and COL11A1 expression levels as well as resistance to cisplatin or paclitaxel. SC66 inhibited phosphorylation of Akt and its downstream effectors 4E-BP1 and p70S6 kinase. SC66 also attenuated expression of TWIST1 and Mcl-1, factors important in cell invasiveness and anti-apoptosis, respectively. SC66 sensitized chemoresistant cells to cisplatin and paclitaxel treatment and promoted apoptosis. In addition, SC66 inhibited COL11A1 expression via decreased binding of CCAAT/enhancer-binding protein beta (c/EBPβ), reducing chemoresistance and decreasing binding of nuclear transcription factor Y (NF-YA) to COL11A1. A mouse xenograft experiment demonstrated that SC66 treatment caused a reduction in tumor formation and enhanced the therapeutic efficacy of cisplatin.
Conclusions: This study demonstrates the role of Akt in ovarian tumor progression and chemoresistance and supports the application of SC66 as a therapy for ovarian cancer.
Citation Format: Yi-Hui Wu, Cheng-Yang Chou. Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3911.
Abstract 3915: YH25248, a selective PI3K delta inhibitor, shows synergistic effect with an anti-PD-L1 antibody
Authors: Park Jinhwi , Kang Ho-Woong , Koo Hyun-Mo , Park Jongsuk , Kim Tae-Wang , Oh Se-Woong , Choi Soongyu 
Published: August 2019

Abstract
Phosphatidylinositol 3-kinase (PI3K) plays critical roles in numerous intracellular processes. Of the four known subtypes, PI3Kδ subtype is primarily expressed in immune cells and has been reported to promote B cell differentiation and regulatory T (Treg) cell activation. Treg cell-mediated immunosuppression is thought to be a major resistance mechanism for immune checkpoint inhibitors. We therefore hypothesized that an effective PI3Kδ inhibitor could enhance anti-cancer immunity when combined with immune checkpoint inhibitors. Through recent efforts, we have discovered YH25248, an oral PI3Kδ-specific inhibitor. YH25248 effectively inhibits PI3Kδ (IC50 = 10nM) showing more than 100-fold selectivity over α, β, and γ subtypes, and exhibited favorable kinase selectivity in 463 kinase panels. In cellular experiments, phospho-AKT was effectively blocked (IC50 = 7 nM), with basophil activation, a known PI3Kδ specific signal, was also inhibited. YH25248 reduced the activity of Treg cells (CD4+/CD25+) isolated from the splenocytes of CT26 tumor-bearing mice, while sparing conventional T cells (CD4+/CD25-). When YH25248 was orally administered (10 mg/kg) to mice, drug exposure in plasma was reasonable, with a half-life of 4.3 hours, while once-daily oral administration of YH25248 (10 ~ 60 mg/kg) significantly inhibited tumor growth of CT26 colon carcinomas in mouse. When the immune cells of tumors were analyzed by flow cytometry, the number of Treg cells was reduced, CD8 + T cells increased. In this model, YH25248 (30 mg/kg, QD) showed synergistic efficacy when combined with an anti-PD-L1 antibody (200 μg/mice, 10F.9G2 clone). In other syngeneic models using 4T1 or MC38 cells, YH25248 (30 mg/kg, QD) also exhibited similar synergistic efficacy in combination with the anti-PD-L1 antibody. In conclusion, YH25248 is a potent, selective, oral inhibitor of PI3Kδ that reduces tumor growth in syngeneic mouse tumor models by increasing the ratio of CD8+ to Treg cells. The combination of YH25248 and anti-PD-L1 antibody resulted in substantially greater tumor growth inhibition in several syngeneic models. These data support the promising potential of YH25248 for combination therapy with immune checkpoint inhibitors to increase therapeutic response rates.
Citation Format: Jinhwi Park, Ho-Woong Kang, Hyun-Mo Koo, Jongsuk Park, Tae-Wang Kim, Se-Woong Oh, Soongyu Choi. YH25248, a selective PI3K delta inhibitor, shows synergistic effect with an anti-PD-L1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3915.