Publications by authors named "Matthew T Burdett"

4 Publications

  • Page 1 of 1

Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors.

Bioorg Med Chem Lett 2010 Jul 25;20(14):4060-4. Epub 2010 May 25.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A pyridazin-4-one fragment 4 (hCatS IC(50)=170 microM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC(50)=430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC(50)=60 nM) and 27 (hCatS IC(50)=40 nM).
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http://dx.doi.org/10.1016/j.bmcl.2010.05.086DOI Listing
July 2010

Identification of potent and novel small-molecule inhibitors of caspase-3.

Bioorg Med Chem Lett 2003 Nov;13(21):3651-5

Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

The design and synthesis of a series of novel, reversible, small molecule inhibitors of caspase-3 are described.
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http://dx.doi.org/10.1016/j.bmcl.2003.08.024DOI Listing
November 2003

In situ assembly of enzyme inhibitors using extended tethering.

Nat Biotechnol 2003 Mar 3;21(3):308-14. Epub 2003 Feb 3.

Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.
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http://dx.doi.org/10.1038/nbt786DOI Listing
March 2003

Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.

J Med Chem 2002 Nov;45(23):5005-22

Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, California 94080, USA.

The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S(4) pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K(i) = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K(i) values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K(i) = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.
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http://dx.doi.org/10.1021/jm020230jDOI Listing
November 2002
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