Anne B. Jefferson
Novartis
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Publication
Featured researches published by Anne B. Jefferson.
Journal of Medicinal Chemistry | 2015
Rama Jain; Michelle Mathur; Jiong Lan; Abran Costales; Gordana Atallah; Savithri Ramurthy; Sharadha Subramanian; Lina Setti; Paul Feucht; Bob Warne; Laura Doyle; Stephen E. Basham; Anne B. Jefferson; Mika Lindvall; Brent A. Appleton; Cynthia Shafer
While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, the full understanding of this kinase family has been restricted by the lack of highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor of the N-terminal kinase of RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted in highly optimized difluorophenol pyridine inhibitors of the RSK kinase family as demonstrated cellularly by the inhibition of YB1 phosphorylation. These compounds provide for the first time in vitro tools with an improved selectivity and potency profile to examine the importance of RSK signaling in cancer cells and to fully evaluate RSK as a therapeutic target.
Molecular Cancer Research | 2014
Ida Aronchik; Brent A. Appleton; Stephen E. Basham; Kenneth Crawford; Mercedita Del Rosario; Laura Doyle; William F. Estacio; Jiong Lan; Mika Lindvall; Catherine A. Luu; Elizabeth Ornelas; Eleni Venetsanakos; Cynthia Shafer; Anne B. Jefferson
The p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases is expressed in a variety of cancers and its substrate phosphorylation has been implicated in direct regulation of cell survival, proliferation, and cell polarity. This study characterizes and presents the most selective and potent RSK inhibitors known to date, LJH685 and LJI308. Structural analysis confirms binding of LJH685 to the RSK2 N-terminal kinase ATP-binding site and reveals that the inhibitor adopts an unusual nonplanar conformation that explains its excellent selectivity for RSK family kinases. LJH685 and LJI308 efficiently inhibit RSK activity in vitro and in cells. Furthermore, cellular inhibition of RSK and its phosphorylation of YB1 on Ser102 correlate closely with inhibition of cell growth, but only in an anchorage-independent growth setting, and in a subset of examined cell lines. Thus, RSK inhibition reveals dynamic functional responses among the inhibitor-sensitive cell lines, underscoring the heterogeneous nature of RSK dependence in cancer. Implications: Two novel potent and selective RSK inhibitors will now allow a full assessment of the potential of RSK as a therapeutic target for oncology. Mol Cancer Res; 12(5); 803–12. ©2014 AACR.
Bioorganic & Medicinal Chemistry Letters | 2014
Abran Costales; Michelle Mathur; Savithri Ramurthy; Jiong Lan; Sharadha Subramanian; Rama Jain; Gordana Atallah; Lina Setti; Mika Lindvall; Brent A. Appleton; Elizabeth Ornelas; Paul Feucht; Bob Warne; Laura Doyle; Stephen E. Basham; Ida Aronchik; Anne B. Jefferson; Cynthia Shafer
2-Amino-7-substituted benzoxazole analogs were identified by HTS as inhibitors of RSK2. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of improving in vitro and target modulation potency and physicochemical properties.
Bioorganic & Medicinal Chemistry Letters | 2018
Rama Jain; Michelle Mathur; Jiong Lan; Abran Costales; Gordana Atallah; Savithri Ramurthy; Sharadha Subramanian; Lina Setti; Paul Feucht; Bob Warne; Laura Doyle; Stephen E. Basham; Anne B. Jefferson; Brent A. Appleton; Mika Lindvall; Cynthia Shafer
Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.
Archive | 2007
Siew Schleyer; Anne B. Jefferson; Judith A. Abraham; W. Michael Kavanaugh
Archive | 2004
Timothy S. Burkoth; Anne B. Jefferson; Christoph Reinhard; Ronald N. Zuckermann
Archive | 2004
Christoph Reinhard; Anne B. Jefferson; Vivien W. Chan
Archive | 2002
Christoph Reinhard; Anne B. Jefferson; Vivien W. Chan
Archive | 2001
Giulia C. Kennedy; Sanmao Kang; Christoph Reinhard; Anne B. Jefferson
Archive | 2004
Christoph Reinhard; Anne B. Jefferson; Vivien W. Chan