An intermolecular, photocatalytic dicarbofunctionalization (DCF) of olefins enabled by the merger of Giese-type addition with Ni/photoredox dual catalysis has been realized. Capitalizing on the rapid addition of 3° radicals to alkenes and their reluctance toward single electron metalation to Ni complexes, regioselective alkylation and arylation of olefins is possible. This dual catalytic method not only permits elaborate species to be assembled from commodity materials, but also allows quaternary and tertiary centers to be installed in a singular, chemoselective olefin difunctionalization. This multicomponent process occurs under exceptionally mild conditions, compatible with a diverse range of functional groups and synthetic handles such as pinacolboronate esters. This technology was directly applied to the synthesis of an intermediate to a preclinical candidate (TK-666) and its derivatives.

26 Nov 2012·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK)

Q1 · MEDICINE

Article

Author: Newman, Joseph V. ; Hentemann, Martin F. ; Hernandez-Juan, Felix A. ; Olivier, Nelson B. ; Read, Jon ; Gowers, Ian K. ; Sheppard, David W. ; Macritchie, Jacqueline A. ; Otterson, Linda G. ; Lazari, Ovadia ; Dumas, Jacques ; Geng, Bolin ; Green, Oluyinka M. ; Martínez-Botella, Gabriel ; Joseph-McCarthy, Diane ; Guler, Satenig ; Keating, Thomas A. ; Owens, Andrew P. ; Breen, John N. ; Larsen, Nicholas A. ; Duffy, James E. S. ; Loch, James T. ; Kawatkar, Sameer ; McKenzie, Andrew R.

Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 μg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.

16 Nov 2012·ACS Chemical BiologyQ2 · BIOLOGY

In Vivo Validation of Thymidylate Kinase (TMK) with a Rationally Designed, Selective Antibacterial Compound

Q2 · BIOLOGY

Article

Author: Hentemann, Martin F. ; Green, Oluyinka M. ; Newman, Joseph V. ; Joseph-McCarthy, Diane ; Guler, Satenig Y. ; Doig, Peter ; Andrews, Beth ; Kutschke, Amy ; Olivier, Nelson B. ; Boriack-Sjodin, P. Ann ; Breen, John N. ; Otterson, Linda G. ; Gangl, Eric ; Martínez-Botella, Gabriel ; Pradeepan, Selvi ; Loch, James T. ; Dumas, Jacques ; Prasad, Swati ; Keating, Thomas A. ; Kawatkar, Sameer ; McKenzie, Andrew R.

There is an urgent need for new antibacterials that pinpoint novel targets and thereby avoid existing resistance mechanisms. We have created novel synthetic antibacterials through structure-based drug design that specifically target bacterial thymidylate kinase (TMK), a nucleotide kinase essential in the DNA synthesis pathway. A high-resolution structure shows compound TK-666 binding partly in the thymidine monophosphate substrate site, but also forming new induced-fit interactions that give picomolar affinity. TK-666 has potent, broad-spectrum Gram-positive microbiological activity (including activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus), bactericidal action with rapid killing kinetics, excellent target selectivity over the human ortholog, and low resistance rates. We demonstrate in vivo efficacy against S. aureus in a murine infected-thigh model. This work presents the first validation of TMK as a compelling antibacterial target and provides a rationale for pursuing novel clinical candidates for treating Gram-positive infections through TMK.

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Indication	Highest Phase	Country/Location	Organization	Date
Gram-Positive Bacterial Infections	Preclinical	United Kingdom	AstraZeneca PLC	24 Oct 2012

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