Targeting Metabolism of Extracellular Nucleotides via Inhibition of Ectonucleotidases CD73 and CD39
In the tumor microenvironment, unusually high concentrations of extracellular adenosine promote tumor proliferation through various immunosuppressive mechanisms. Blocking adenosine production by inhibiting nucleotide-metabolizing enzymes, such as ectonucleotidases CD73 and CD39, represents a promisi...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-11, Vol.63 (22), p.13444-13465 |
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| container_end_page | 13465 |
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| container_issue | 22 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 63 |
| creator | Jeffrey, Jenna L Lawson, Kenneth V Powers, Jay P |
| description | In the tumor microenvironment, unusually high concentrations of extracellular adenosine promote tumor proliferation through various immunosuppressive mechanisms. Blocking adenosine production by inhibiting nucleotide-metabolizing enzymes, such as ectonucleotidases CD73 and CD39, represents a promising therapeutic strategy that may synergize with other immuno-oncology mechanisms and chemotherapies. Emerging small-molecule ectonucleotidase inhibitors have recently entered clinical trials. This Perspective will outline challenges, strategies, and recent advancements in targeting this class with small-molecule inhibitors, including AB680, the first small-molecule CD73 inhibitor to enter clinical development. Specific case studies, including structure-based drug design and lead optimization, will be outlined. Preclinical data on these molecules and their ability to enhance antitumor immunity will be discussed. |
| doi_str_mv | 10.1021/acs.jmedchem.0c01044 |
| format | Article |
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Blocking adenosine production by inhibiting nucleotide-metabolizing enzymes, such as ectonucleotidases CD73 and CD39, represents a promising therapeutic strategy that may synergize with other immuno-oncology mechanisms and chemotherapies. Emerging small-molecule ectonucleotidase inhibitors have recently entered clinical trials. This Perspective will outline challenges, strategies, and recent advancements in targeting this class with small-molecule inhibitors, including AB680, the first small-molecule CD73 inhibitor to enter clinical development. Specific case studies, including structure-based drug design and lead optimization, will be outlined. 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Med. Chem</addtitle><description>In the tumor microenvironment, unusually high concentrations of extracellular adenosine promote tumor proliferation through various immunosuppressive mechanisms. Blocking adenosine production by inhibiting nucleotide-metabolizing enzymes, such as ectonucleotidases CD73 and CD39, represents a promising therapeutic strategy that may synergize with other immuno-oncology mechanisms and chemotherapies. Emerging small-molecule ectonucleotidase inhibitors have recently entered clinical trials. This Perspective will outline challenges, strategies, and recent advancements in targeting this class with small-molecule inhibitors, including AB680, the first small-molecule CD73 inhibitor to enter clinical development. Specific case studies, including structure-based drug design and lead optimization, will be outlined. 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Med. Chem</addtitle><date>2020-11-25</date><risdate>2020</risdate><volume>63</volume><issue>22</issue><spage>13444</spage><epage>13465</epage><pages>13444-13465</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>In the tumor microenvironment, unusually high concentrations of extracellular adenosine promote tumor proliferation through various immunosuppressive mechanisms. Blocking adenosine production by inhibiting nucleotide-metabolizing enzymes, such as ectonucleotidases CD73 and CD39, represents a promising therapeutic strategy that may synergize with other immuno-oncology mechanisms and chemotherapies. Emerging small-molecule ectonucleotidase inhibitors have recently entered clinical trials. This Perspective will outline challenges, strategies, and recent advancements in targeting this class with small-molecule inhibitors, including AB680, the first small-molecule CD73 inhibitor to enter clinical development. 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| subjects | 5'-Nucleotidase - antagonists & inhibitors 5'-Nucleotidase - chemistry 5'-Nucleotidase - metabolism Antineoplastic Agents - administration & dosage Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Apyrase - antagonists & inhibitors Apyrase - chemistry Apyrase - metabolism Drug Delivery Systems - methods Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism GPI-Linked Proteins - antagonists & inhibitors GPI-Linked Proteins - chemistry GPI-Linked Proteins - metabolism Humans Nucleotides - antagonists & inhibitors Nucleotides - chemistry Nucleotides - metabolism Protein Structure, Secondary |
| title | Targeting Metabolism of Extracellular Nucleotides via Inhibition of Ectonucleotidases CD73 and CD39 |
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