James Christensen

Publications (3)19.28 Total impact

• Article: Correction to Discovery of a Novel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor (c-MET) Protein Kinase Inhibitors and Identification of the Clinical Candidate 2-(4-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the Treatment of Cancer.

  J Jean Cui, Michele McTigue, Mitchell Nambu, Michelle Tran-Dubé, Mason Pairish, Hong Shen, Lei Jia, Hengmiao Cheng, Jacqui Hoffman, Phuong Le, [......], Neil Grodsky, Ya-Li Deng, Max Parker, Sergei Timofeevski, Brion W Murray, Shinji Yamazaki, Shirley Aguirre, Qiuhua Li, Helen Zou, James Christensen
  Journal of Medicinal Chemistry 10/2012; · 4.80 Impact Factor
• Article: Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK).

  J Jean Cui, Michelle Tran-Dubé, Hong Shen, Mitchell Nambu, Pei-Pei Kung, Mason Pairish, Lei Jia, Jerry Meng, Lee Funk, Iriny Botrous, [......], Gordon Alton, Sergei Timofeevski, Shinji Yamazaki, Qiuhua Li, Helen Zou, James Christensen, Barbara Mroczkowski, Steve Bender, Robert S Kania, Martin P Edwards
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  ABSTRACT: Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.
  Journal of Medicinal Chemistry 08/2011; 54(18):6342-63. · 4.80 Impact Factor
• Article: KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.

  Ketan S Gajiwala, Joe C Wu, James Christensen, Gayatri D Deshmukh, Wade Diehl, Jonathan P DiNitto, Jessie M English, Michael J Greig, You-Ai He, Suzanne L Jacques, [......], David Molina, Terri Quenzer, Peter A Wells, Xiu Yu, Yan Zhang, Aihua Zou, Mark R Emmett, Alan G Marshall, Hui-Min Zhang, George D Demetri
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  ABSTRACT: Most gastrointestinal stromal tumors (GISTs) exhibit aberrant activation of the receptor tyrosine kinase (RTK) KIT. The efficacy of the inhibitors imatinib mesylate and sunitinib malate in GIST patients has been linked to their inhibition of these mutant KIT proteins. However, patients on imatinib can acquire secondary KIT mutations that render the protein insensitive to the inhibitor. Sunitinib has shown efficacy against certain imatinib-resistant mutants, although a subset that resides in the activation loop, including D816H/V, remains resistant. Biochemical and structural studies were undertaken to determine the molecular basis of sunitinib resistance. Our results show that sunitinib targets the autoinhibited conformation of WT KIT and that the D816H mutant undergoes a shift in conformational equilibrium toward the active state. These findings provide a structural and enzymologic explanation for the resistance profile observed with the KIT inhibitors. Prospectively, they have implications for understanding oncogenic kinase mutants and for circumventing drug resistance.
  Proceedings of the National Academy of Sciences 02/2009; 106(5):1542-7. · 9.68 Impact Factor