Margit Hagel
Celgene
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Featured researches published by Margit Hagel.
Cancer Discovery | 2015
Margit Hagel; Chandra Miduturu; Michael Sheets; Nooreen Rubin; Weifan Weng; Nicolas Stransky; Neil Bifulco; Joseph L. Kim; Brian L. Hodous; Natasja Brooijmans; Adam Shutes; Christopher Winter; Christoph Lengauer; Nancy E. Kohl; Timothy J. Guzi
UNLABELLED Aberrant signaling through the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR 4) signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and has been implicated to play a similar role in humans. We have developed BLU9931, a potent and irreversible small-molecule inhibitor of FGFR4, as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification. Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho β (KLB) could potentially respond to treatment with an FGFR4 inhibitor. These findings are the first demonstration of a therapeutic strategy that targets a subset of patients with HCC. SIGNIFICANCE This article documents the discovery of BLU9931, a novel irreversible kinase inhibitor that specifically targets FGFR4 while sparing all other FGFR paralogs and demonstrates exquisite kinome selectivity. BLU9931 is efficacious in tumors with an intact FGFR4 signaling pathway that includes FGF19, FGFR4, and KLB. BLU9931 is the first FGFR4-selective molecule for the treatment of patients with HCC with aberrant FGFR4 signaling.
Nature Chemical Biology | 2011
Margit Hagel; Deqiang Niu; Thia St. Martin; Michael Sheets; Lixin Qiao; Hugues Bernard; Russell Karp; Zhendong Zhu; Matthew T. Labenski; Prasoon Chaturvedi; Mariana Nacht; William F. Westlin; Russell C. Petter; Juswinder Singh
Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
MedChemComm | 2012
Juswinder Singh; Erica Evans; Margit Hagel; Matthew Labinski; Alex Dubrovskiy; M. Nacht; Russell C. Petter; Aravind Prasad; Michael Sheets; Thia St Martin; Robert Tjin Tham Sjin; William F. Westlin; Zhendong Zhu
Recently, the importance of targeted covalent inhibitors in addressing potency, selectivity and drug resistance has become of great interest, especially in the area of non-small cell lung cancer (NSCLC). Although several covalent EGFR TKIs that are advancing in NSCLC clinical development are active against mutations which are refractory to the reversible TKI drugs Tarceva and Iressa, limited chemical diversity has been explored; all of the irreversible and reversible clinical compounds share the same quinazoline scaffold. We describe the design of a novel pyrimidine-based irreversible inhibitor of EGFR (CNX17) which is active against both the WT EGFR as well as the resistance mutation L858R/T790M in biochemical assays. The inhibitor is also a potent inhibitor of EGFR signaling, including the L858R/T790M resistance mutation in cells (H1975 cell line, EC50 441 nM). Importantly, it also potently inhibits proliferation in both HCC827 (EGFRΔ746–750 EC50 < 5 nM) and H1975 (EC50 134 nM). This novel chemical scaffold may be an important addition to the armamentarium in overcoming drug resistance to current EGFR therapies.
Cancer Research | 2014
Margit Hagel; Chandra Miduturu; Mike Sheets; Weifan Weng; Nooreen Rubin; Neil Bifulco; Lucian Dipietro; Joseph Kim; Natasja Brooijmans; Nicolas Stransky; Christopher Winter; Christoph Lengauer; Timothy J. Guzi
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Chemotherapy has proven ineffective, and Sorafenib remains the only approved targeted drug with no second or third line treatment options. Sorafenib slows the growth of advanced liver cancers and helps some patients live longer - by an average of about three months. There is a pressing need for more effective therapies. FGF19 is a highly controlled hormone normally expressed in the intestine, that acts in the liver to regulate bile acid synthesis and hepatocyte proliferation via activation of FGFR4. In 7% of patients with HCC, FGF19 is contained within a focal amplification on chromosome 11q13.3. Overexpression of FGF19 in transgenic mice produces liver tumors which are sensitive to treatment with a FGFR4 tool antibody. Additionally, the growth of tumor cells in xenograft models with FGF19 amplification is dependent on FGFR4 signaling. Thus, selective inhibition of FGFR4 might represent a viable strategy for treating this genetically defined subgroup of HCC patients. Herein, we describe our efforts to identify an ultraselective small molecule inhibitor of FGFR4 which spares the other FGFR isoforms with the intent to avoid FGFR1-3 driven, dose limiting toxicities like soft tissue mineralization. Utilizing structure based drug design, we prepared a series of inhibitor templates designed to covalently modify a target cysteine residue present in FGFR4, but not the other FGFR isoforms. Optimization of one of these templates led to the identification of BLU9931, a highly potent and exquisitely selective, covalent inhibitor of FGFR4. BLU9931 persistently inhibits FGFR4 mediated signaling in cancer cells as evidenced by decreased phosphorylation of FRS2 and ERK. Importantly, BLU9931 does not block signaling driven by FGFR1. Upon oral dosing in mice, BLU9931 is well tolerated and demonstrates robust and dose dependent induction of the FGFR4 target gene CYP7a1 in Hep3B cells, a FGF19 amplified HCC xenograft model. Upon extended dosing, BLU9931 causes sustained regression of tumors, including complete responses. We then explored if HCCs with alterations other than FGF19 amplification are also dependent on FGFR4 signaling. Dosing of molecularly annotated patient derived HCC xenografts with BLU9931 suggests that selective targeting of FGFR4 represents a viable option for the treatment of an expanded population segment of genomically defined HCC patients, much larger than originally anticipated. Citation Format: Margit Hagel, Chandra Miduturu, Mike Sheets, Weifan Weng, Nooreen Rubin, Neil Bifulco, Lucian DiPietro, Joseph Kim, Natasja Brooijmans, Nicolas Stransky, Christopher Winter, Christoph Lengauer, Timothy Guzi. First isoform selective inhibitor of FGFR4 for the treatment of genomically defined patients with hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-324. doi:10.1158/1538-7445.AM2014-LB-324
Archive | 2009
Margit Hagel; Thia St Martin; M. Nacht
Journal of Hepatology | 2010
Deqiang Niu; Margit Hagel; Lixin Qiao; T. St. Martin; Michael Sheets; Prasoon Chaturvedi; Matthew T. Labenski; M. Nacht; William F. Westlin; Russell C. Petter; Juswinder Singh
Journal of Hepatology | 2015
K. Hoeflich; Margit Hagel; C. Miduturu; Michael Sheets; N. Rubin; W. Weng; N. Stransky; N. Bifulco; J. Kim; B. Hodous; N. Brooijmans; A. Shutes; C. Winter; C. Lengauer; N. Kohl; T. Guzi
The FASEB Journal | 2010
Russell C. Petter; Margit Hagel; Deqiang Niu; Thia St. Martin; Michael Sheets; Lixin Qiao; Hugues Bernhard; Russell Karp; Zhendong Zhu; Matthew T. Labenski; Prasson Chaturvedi; Mariana Nacht; William F. Westlin; Juswinder Singh
Archive | 2010
Margit Hagel; Deqiang Niu; T. St.Martin; Michael Sheets; Lixin Qiao; Hugues Bernard; Russell Karp; Zhiming Zhu; Matthew T. Labenski; Prasoon Chaturvedi; M. Nacht; William F. Westlin; Russell C. Petter; Juswinder Singh
Journal of Hepatology | 2010
Margit Hagel; Deqiang Niu; T. St. Martin; Michael Sheets; Lixin Qiao; Prasoon Chaturvedi; Matthew T. Labenski; M. Nacht; Russell C. Petter; Juswinder Singh; William F. Westlin