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Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein…
Through screening and lead optimization using the human PERK crystal structure, compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor is discovered, which inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.
- J. Axten, S. P. Romeril, Rakesh Kumar
- Biology, ChemistryACS Medicinal Chemistry Letters
- 23 August 2013
In continuation of the drug discovery program, a strategy to decrease inhibitor lipophilicity is applied as a means to improve physical properties and pharmacokinetics and is selected for advancement to preclinical development.
Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors.
- J. Medina, C. J. Becker, J. Axten
- Biology, ChemistryJournal of medicinal chemistry
- 22 February 2011
The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines, demonstrating the utility of these molecules as tools to further delineate the biology ofPDK1 and the potential pharmacological uses of a PDK 1 inhibitor.
Aminoindazole PDK1 Inhibitors: A Case Study in Fragment-Based Drug Discovery.
- J. Medina, C. Blackledge, J. Axten
- Chemistry, BiologyACS Medicinal Chemistry Letters
- 22 July 2010
Well-defined structure-activity relationships and protein crystallography provide a basis for further elaboration and optimization of aminoindazole 19 as a PDK1 inhibitor.
Selective 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitors: dissecting the function and pharmacology of PDK1.
- J. Medina
- Biology, ChemistryJournal of medicinal chemistry
- 15 March 2013
The discovery of potent and selective small molecule PDK1 inhibitors are reviewed and their value in cellular studies, the understanding of PDK3-Phosphoinositide-dependent protein kinase 1 biology, and the impact on the therapeutic potential in cancer are highlighted.
9-Borabicyclo[3.3.2]decanes and the asymmetric hydroboration of 1,1-disubstituted alkenes.
- A. Z. González, José G. Román, J. Soderquist
- ChemistryJournal of the American Chemical Society
- 27 June 2008
These reagents exhibit unprecedented levels of selectivity in the asymmetric hydroboration of 1,1-disubstituted alkenes (28-92% ee), a previously unanswered challenge in the nearly 50 year history of this reagent-controlled process.
Benzyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate, a versatile intermediate for the synthesis of 3,3-dimethylproline derivatives.
- J. Medina, C. Blackledge, K. Erhard, J. Axten, W. Miller
- ChemistryThe Journal of organic chemistry
- 23 April 2008
The synthesis of racemic nitrile (+/-)-9 was accomplished in four steps and 58% overall yield from the known pyrrolidinone 5.1% via preparative chiral HPLC to afford optically pure nitriles.
Discovery of a new series of Aurora inhibitors through truncation of GSK1070916.
- J. Medina, Seth W. Grant, H. Xiang
- Chemistry, BiologyBioorganic & medicinal chemistry letters
- 15 April 2010
New direct 11B NMR-based analysis of organoboranes through their potassium borohydrides.
- J. Medina, Gabriel Cruz, C. Cabrera, J. Soderquist
- ChemistryThe Journal of organic chemistry
- 14 May 2003
Previously unknown details of pinene-based hydroborations and reductions are revealed for the first time employing the KH (11)B NMR technique.
Acylprolinamides: a new class of peptide deformylase inhibitors with in vivo antibacterial activity.
- J. Axten, J. Medina, N. Campobasso
- Chemistry, BiologyBioorganic & medicinal chemistry letters
- 15 June 2012
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