作者: Moris, Francisco ; Santos, Laura ; Estupiñan, Oscar ; Menendez, Sofia T ; Perez‐Escuredo, Jhudit ; Fernandez‐Nevado, Lucia ; Tornin, Juan ; Allonca, Eva ; Braña, Alejandro ; Hermosilla, Maria Ana ; Rey, Veronica ; Fernandez‐Garcia, Maria Teresa ; Alvarez‐Fernandez, Carlos ; Oro, Patricia ; Costales, Paula ; Astudillo, Aurora ; Rodriguez, Rene ; Rodriguez, Aida

Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro‐tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro‐tumoral kinases. Therefore, we studied the antitumor activity of EC‐70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro‐survival kinases. Evaluation of the phospho‐kinase profile in cell‐of‐origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC‐70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC‐70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC‐70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC‐70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatments.

2018-03-01·Molecular Cancer Therapeutics2区 · 医学

Inhibition of FLT3 and PIM Kinases by EC-70124 Exerts Potent Activity in Preclinical Models of Acute Myeloid Leukemia

2区 · 医学

Article

作者: Oro, Patricia ; Rodríguez, Carmen ; Ríos-Lombardía, Nicolás ; Luño, Elisa ; Costales, Paula ; Martín, Vanesa ; Núñez, Luz-Elena ; Pérez-Escuredo, Jhudit ; Sanchez-Sanchez, Ana M. ; Morís, Francisco ; Antolín, Isaac ; Puente-Moncada, Noelia ; Hermosilla, Maria Ana

AbstractInternal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myelogenous leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here, we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as PIM kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell-cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared with midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate inhibition of FLT3-STAT5, Akt-mTOR-S6, and PIM-BAD pathways. Oral administration of EC-70124 in FLT3-ITD xenograft models demonstrates high efficacy, reaching complete tumor regression. Ex vivo, EC-70124 impaired cell viability in leukemic blasts, especially from FLT3-ITD patients. Our results demonstrate the ability of EC-70124 to reduce proliferation and induce cell death in AML cell lines, patient-derived leukemic blast and xenograft animal models, reaching best results in FLT3 mutants that carry other molecular pathways' alterations. Thus, its unique inhibition profile warrants EC-70124 as a promising agent for AML treatment based on its ability to interfere the complex oncogenic events activated in AML at several levels. Mol Cancer Ther; 17(3); 614–24. ©2018 AACR.

2016-05-01·Molecular Cancer Therapeutics2区 · 医学

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

2区 · 医学

Article

作者: Costales, Paula ; Longoni, Nicole ; Catapano, Carlo V. ; Dallavalle, Cecilia ; Civenni, Gianluca ; Morís, Francisco ; García Inclán, Cristina ; Albino, Domenico ; Nuñez, Luz Elena ; Carbone, Giuseppina M.

AbstractCancer stem cells (CSC) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-κB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs. EC-70124 is a novel chimeric indolocarbazole compound generated by metabolic engineering of the biosynthetic pathways of glycosylated indolocarbazoles, such as staurosporine and rebeccamycin. In vitro kinome analyses revealed that EC-70124 acted as a multikinase inhibitor with potent activity against IKKβ and JAK2. In this study, we show that EC-70124 blocked concomitantly NF-κB and STAT3 in prostate cancer cells and particularly prostate CSCs, which exhibited overactivation of these transcription factors. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKβ and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice. Furthermore, the drug blocked activation of NF-κB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro and delayed development of prostate tumor xenografts. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo. Thus, EC-70124 is a potent inhibitor of the NF-κB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs. EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer. Mol Cancer Ther; 15(5); 806–18. ©2016 AACR.

项与 EC-70124 相关的新闻（医药）

2022-04-28

·entrechem.com

AI-Therapeutics acquires the preclinical drugs EC-8042 and EC-70124 from EntreChem SL

The pharmaceutical company AI-Therapeutics (Guilford, CT, USA) has acquired the preclinical drug candidates EC-8042 and EC-70124 in the course of the insolvency proceedings EntreChem was experiencing since February of last year. The insolvency event left unfinished the development of both drugs, that were on the verge of facing the first tests in humans. One of them, EC-8042, shows strong data in various types of pediatric sarcomas, especially EWS and rhabdoid tumors. The other one, EC-70124 is a multikinase inhibitor with superior profile to the standard of care in AML. The transaction brings as a result that the vast majority of creditors will recoup the debt. Development of the drugs will continue in the USA. AI-Therapeutics belongs to Jonathan Rothberg, a serial entrepreneur involved in many start-ups. A recipient of the National Medal of Technology and Innovation. Dr. Jonathan Rothberg is the founder of several companies in the scientific and medical sector, including CuraGen, 454 Life Sciences, Ion Torrent y 4Bionics. Notably, Next Generation Sequencing companies 454 Life Sciences and IonTorrent launched a new era in genomics and precision medicine.

并购

2016-03-10

·entrechem.com

EntreChem’s orally active EC-70124 reverts tumorigenic and stem cell properties in prostate cancer

Cancer stem cells (CSCs) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-κB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs. EC-70124, is a potent dual inhibitor of the NF-kB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs, which exhibited over-activation of these transcription factors. The results of a collaborative research from EntreChem SL (Oviedo), and the Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR, Bellinzona, Switzerland), focused on searching new strategies against prostate cancer, the most common epithelial cancer and the third leading cause of cancer death in men in western countries, have been published in the journal Molecular Cancer Therapeutics. The research, directed by Dr. Carlo Catapano (IOR), focuses on the frequently activated STAT3 and NF-kB transcription factors and their blocking by the multi-kinase inhibitor EC-70124 both in tumorigenic and cancer stem cells populations of prostate cancer cells. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKb and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice. Furthermore, the drug blocked activation of NF-κB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo. EC-70124 in vivo, when dosed orally, significantly delayed tumor growth without signs of toxicity, and treatment with the drug reduced both pIkb and pSTAT3 levels in the tumors of treated mice, confirming the effect of the drug in the NF-κB and STAT3 pathways. Collectively, these findings underscore the ability of EC-70124 to act as a dual inhibitor of STAT3 and NF-κB signaling in vitro and in vivo. This novel kinase inhibitor with its action on two key signaling pathways may represent the prototype of a new class of anticancer drugs with ability to interfere with CSCs in prostate tumors providing tools for innovative approaches for treatment of advanced prostate cancer. For full details, see: Civenni G et al, EC-70124, a novel glycosylated indolocarbazole multi-kinase inhibitor, reverts tumorigenic and stem cell properties in prostate cancer by inhibiting STAT3 and NF-kB, Mol. Cancer. Ther. 2016; pii: molcanther.0791.2015. EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer. Molecular Cancer Therapeutics is a monthly journal that emphasizes preclinical development of novel cancer therapeutic agents and innovative tools & technologies for drug discovery. EC-870124 is a hybrid natural product obtained by combinatorial biosynthesis from genetically modified bacteria, and are currently in advanced preclinical studies by EntreChem S.L. (not available yet for trials in humans). EntreChem SL is a Spanish spin off from the University of Oviedo, and its shareholders include original co-founders and local family offices. Private financing is complemented by public funds from MINECO, Genome Spain Foundation (now FECYT), FICYT, IDEPA, SRP and the 7FP and H2020 from the European Union. More information: Dr. Carlo Catapano: carlo.catapano@ior.iosi.ch, +41 091 820 0365 Dr. Francisco Morís: fmv@entrechem.com, +34 985 259 021 and also: IOR: http://ior.iosi.ch/site/?facstaff=carlo-catapano-md EntreChem SL: www.entrechem.com

临床1期

2015-12-21

·entrechem.com

New EntreChem publication in Oncotarget describing activity of EC-70124 in colorectal cancer

Activated kinases were identified by using phosphokinase arrays with human colorectal tumor samples, including the Epidermal Growth Factor Receptor (EGFR), components of the PI3K/mTOR pathway (AKT and S6), and SRC, among others. EC-7012, a kinase inhibitor, shows high in vitro antiproliferative activity as well as cell migration inhibition. Major effects are related to targeting of the PI3K/mTOR pathway and SRC. The combination with standards of care is synergistic in vitro, and also reduced tumor growth in vivo and inhibited pS6 in the implanted tumors, offering opportunities for combination therapy with drugs currently in clinical use. The results of a collaborative research from EntreChem SL (Oviedo), the Translational Cancer Research Unit at Albacete University Hospital, CHUA (Albacete, Spain) and the Translational Oncopharmacology Unit of CIC (Salamanca, Spain) focused on searching new strategies for colorectal cancer, which accounts for approximately 9% of all cancer incidence, have been published in the journal Oncotarget. The research, directed by Dr. Alberto Ocaña (CHUA), with participation from Dr. Atanasio Pandiella (CIC) focuses on receptor tyrosine kinases (RTKs) downstream signaling pathways involved in the regulation of proliferation and survival, like PI3K/mTOR, and SRC. EC-70124 shows in vitro antiprolife rative and antimigration effects mediated by simultaneous inhibition of the PI3K/mTOR signaling pathway and SRC, and also by DNA damage induction, causing cell cycle arrest on G2/M. EC-70124 in vivo, when dosed intravenously, significantly delayed tumor growth without signs of toxicity, and treatment with the drug reduced pS6 levels at different timepoints, confirming the effect of the drug in the PI3K/mTOR pathway Most current therapeutic strategies in oncology are based on drug combinations, therefore identification of synergistic interactions between targeted agents and chemotherapies is a main goal. Studies in combination with standards of care showed synergy with chemotherapeutic agents like irinotecan, oxaliplatin and 5-fluorouracil raising the possibility to explore these combinations in the clinical setting. For full details, see: Serrano-Heras G et al, Phospho-kinase profile of colorectal tumors guides in the selection of multi-kinase inhibitors. Oncotarget 2015; 6(31): 31272-83. The prognosis of colorectal cancer is poor due to the limited therapeutic options and the lack of specific targeted agents. The multitargeted kinase inhibitor EC-70124 shows activity in RTKs and their downstream routes, and combines synergistically with several current standards of care, so EC-70124 represents an opportunity to explore a polypharmacology approach in colorectal cancer. Oncotarget ia a multidisciplinary traditional journal with free-access. Oncotarget mission is to make scientific results rapidly and widely available. The journal helps all researchers contribute to the progress of science. EC-70124 is a hybrid natural product obtained by combinatorial biosynthesis from genetically modified bacteria, and are currently in advanced preclinical studies by EntreChem SL (not available yet for trials in humans). EntreChem SL is a Spanish spin off from the University of Oviedo, and its shareholders include original co-founders and local family offices. Private financing is complemented by public funds from MINECO, Genome Spain Foundation (now FECYT), FICYT, IDEPA, SRP and the 7FP and H2020 from the European Union. More information: Dr. Alberto Ocaña: albertoo@sescam.jccm.es, +34 967 597 100, ext. 37087 Dr. Atanasio Pandiella: atanasio@usal.es, +34 923 294 815 Dr. Francisco Morís: fmv@entrechem.com, +34 985 259 021 and also: CHUA: www.chospab.es/investigacion/oncologia_traslacional/intro.htm CIC: www.cicancer.org EntreChem SL: www.entrechem.com

临床1期临床结果AACR会议

100 项与 EC-70124 相关的药物交易

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