145736-69-2Relevant academic research and scientific papers
Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability
Nomme, Julian,Li, Zheng,Gipson, Raymond M.,Wang, Jue,Armijo, Amanda L.,Le, Thuc,Poddar, Soumya,Smith, Tony,Santarsiero, Bernard D.,Nguyen, Hien-Anh,Czernin, Johannes,Alexandrova, Anastassia N.,Jung, Michael E.,Radu, Caius G.,Lavie, Arnon
, p. 9480 - 9494 (2014)
Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers.
DEOXYCYTIDINE KINASE INHIBITORS
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Paragraph 0367, (2015/02/25)
Provided herein are compounds that bind to dCK and methods for treating cancer.
Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography
Murphy, Jennifer M.,Armijo, Amanda L.,Nomme, Julian,Lee, Chi Hang,Smith, Quentin A.,Li, Zheng,Campbell, Dean O.,Liao, Hsiang-I.,Nathanson, David A.,Austin, Wayne R.,Lee, Jason T.,Darvish, Ryan,Wei, Liu,Wang, Jue,Su, Ying,Damoiseaux, Robert,Sadeghi, Saman,Phelps, Michael E.,Herschman, Harvey R.,Czernin, Johannes,Alexandrova, Anastassia N.,Jung, Michael E.,Lavie, Arnon,Radu, Caius G.
supporting information, p. 6696 - 6708 (2013/10/01)
Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest, and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using 18F-L-1-(2′-deoxy-2′-FluoroArabinofuranosyl) Cytosine (18F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC50 = ～1-12 nM) using the 18F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy.
