Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors

We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (<b>10d</b> and (<i>S</i>)-<b>17b</b>) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound <b>5</b> in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., <b>10a</b> and <b>10b</b>). After demonstrating that the pharmacophores of the chelating inhibitors (<i>S</i>)-<b>10a</b>, (<i>R</i>)-<b>10a</b>, and <b>10b</b> were binding within the MMP-13 active site, the Zn²⁺ chelating unit was replaced with nonchelating polar residues that bridged over the Zn²⁺ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors <b>10d</b> and (<i>S</i>)-<b>17b</b>, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn²⁺ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs

Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors

We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (<b>10d</b> and (<i>S</i>)-<b>17b</b>) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound <b>5</b> in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., <b>10a</b> and <b>10b</b>). After demonstrating that the pharmacophores of the chelating inhibitors (<i>S</i>)-<b>10a</b>, (<i>R</i>)-<b>10a</b>, and <b>10b</b> were binding within the MMP-13 active site, the Zn²⁺ chelating unit was replaced with nonchelating polar residues that bridged over the Zn²⁺ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors <b>10d</b> and (<i>S</i>)-<b>17b</b>, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn²⁺ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs

Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors

We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (<b>10d</b> and (<i>S</i>)-<b>17b</b>) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound <b>5</b> in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., <b>10a</b> and <b>10b</b>). After demonstrating that the pharmacophores of the chelating inhibitors (<i>S</i>)-<b>10a</b>, (<i>R</i>)-<b>10a</b>, and <b>10b</b> were binding within the MMP-13 active site, the Zn²⁺ chelating unit was replaced with nonchelating polar residues that bridged over the Zn²⁺ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors <b>10d</b> and (<i>S</i>)-<b>17b</b>, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn²⁺ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs

Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors

We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (<b>10d</b> and (<i>S</i>)-<b>17b</b>) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound <b>5</b> in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., <b>10a</b> and <b>10b</b>). After demonstrating that the pharmacophores of the chelating inhibitors (<i>S</i>)-<b>10a</b>, (<i>R</i>)-<b>10a</b>, and <b>10b</b> were binding within the MMP-13 active site, the Zn²⁺ chelating unit was replaced with nonchelating polar residues that bridged over the Zn²⁺ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors <b>10d</b> and (<i>S</i>)-<b>17b</b>, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn²⁺ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs

Novel Pyrrolidine Diketopiperazines Selectively Inhibit Melanoma Cells via Induction of Late-Onset Apoptosis

A common liability of cancer drugs is toxicity to noncancerous cells. Thus, molecules are needed that are potent toward cancer cells while sparing healthy cells. The cost of traditional cell-based HTS is dictated by the library size, which is typically in the hundreds of thousands of individual compounds. Mixture-based combinatorial libraries offer a cost-effective alternative to single-compound libraries while eliminating the need for molecular target validation. Presently, lung cancer and melanoma cells were screened in parallel with healthy cells using a mixture-based library. A novel class of compounds was discovered that selectively inhibited melanoma cell growth via apoptosis with submicromolar potency while sparing healthy cells. Additionally, the cost of screening and biological follow-up experiments was significantly lower than in typical HTS. Our findings suggest that mixture-based phenotypic HTS can significantly reduce cost and hit-to-lead time while yielding novel compounds with promising pharmacology