Mechanistic and inhibition studies on isocitrate dehydrogenase 1
<p>Genes encoding for IDH1 and IDH2 are frequently mutated in multiple cancer types including gliomas and AML. IDH variants, notably R132H IDH1, result in a gain-offunction leading to substantially enhanced production of the ‘oncometabolite’, 2- hydroxyglutarate. Drug development by pharmaceut...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2019
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| _version_ | 1811139551952896000 |
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| author | Liu, S |
| author2 | Schofield, C |
| author_facet | Schofield, C Liu, S |
| author_sort | Liu, S |
| collection | OXFORD |
| description | <p>Genes encoding for IDH1 and IDH2 are frequently mutated in multiple cancer types including gliomas and AML. IDH variants, notably R132H IDH1, result in a gain-offunction leading to substantially enhanced production of the ‘oncometabolite’, 2- hydroxyglutarate. Drug development by pharmaceutical companies has yielded potent R132H IDH1 inhibitors, unusually nearly all of which work by an allosteric mechanism, implying undetermined processes during substrate and inhibitor binding to IDH1. Mechanistic studies revealed the fundamental role of metal ions in facilitating substrate binding to wt IDH1 and R132H IDH1. DOSY NMR experiments revealed structures of such metabolite-metal ion complexes in solution that are distinct from the published X-ray crystal structures. The studies also suggested that R132H IDH1 selective inhibitors likely work by displacing the protein-bound metal ion, providing the mechanistic basis for mutant IDH inhibition and the opportunities for improved therapies through metal ion interference. Comparative studies on clinically relevant mIDH inhibitors showed that the mIDH1 inhibitors bind to wt IDH1 and R132H IDH1 with similar binding affinities despite their inhibitory selectivity for the variant. In light of the recently emerged resistance to IDH targeting drugs, several novel therapeutic strategies for treating IDH malignancies were then investigated, including the targeted degradation of R132H IDH1, covalent inhibition of R132H IDH1 through selective cysteine-reacting inhibitors, as well as exploiting substrate analogues as active site binding inhibitors. It is hoped that both the mechanistic and inhibition studies described in this work will help enable the development of improved therapies targeting IDH.</p> |
| first_indexed | 2024-09-25T04:07:54Z |
| format | Thesis |
| id | oxford-uuid:ccfa1c83-c2c7-44b8-a62b-423fc0b6c192 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:07:54Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:ccfa1c83-c2c7-44b8-a62b-423fc0b6c1922024-05-31T08:27:40ZMechanistic and inhibition studies on isocitrate dehydrogenase 1Thesishttp://purl.org/coar/resource_type/c_db06uuid:ccfa1c83-c2c7-44b8-a62b-423fc0b6c192EnglishORA Deposit2019Liu, SSchofield, C<p>Genes encoding for IDH1 and IDH2 are frequently mutated in multiple cancer types including gliomas and AML. IDH variants, notably R132H IDH1, result in a gain-offunction leading to substantially enhanced production of the ‘oncometabolite’, 2- hydroxyglutarate. Drug development by pharmaceutical companies has yielded potent R132H IDH1 inhibitors, unusually nearly all of which work by an allosteric mechanism, implying undetermined processes during substrate and inhibitor binding to IDH1. Mechanistic studies revealed the fundamental role of metal ions in facilitating substrate binding to wt IDH1 and R132H IDH1. DOSY NMR experiments revealed structures of such metabolite-metal ion complexes in solution that are distinct from the published X-ray crystal structures. The studies also suggested that R132H IDH1 selective inhibitors likely work by displacing the protein-bound metal ion, providing the mechanistic basis for mutant IDH inhibition and the opportunities for improved therapies through metal ion interference. Comparative studies on clinically relevant mIDH inhibitors showed that the mIDH1 inhibitors bind to wt IDH1 and R132H IDH1 with similar binding affinities despite their inhibitory selectivity for the variant. In light of the recently emerged resistance to IDH targeting drugs, several novel therapeutic strategies for treating IDH malignancies were then investigated, including the targeted degradation of R132H IDH1, covalent inhibition of R132H IDH1 through selective cysteine-reacting inhibitors, as well as exploiting substrate analogues as active site binding inhibitors. It is hoped that both the mechanistic and inhibition studies described in this work will help enable the development of improved therapies targeting IDH.</p> |
| spellingShingle | Liu, S Mechanistic and inhibition studies on isocitrate dehydrogenase 1 |
| title | Mechanistic and inhibition studies on isocitrate dehydrogenase 1 |
| title_full | Mechanistic and inhibition studies on isocitrate dehydrogenase 1 |
| title_fullStr | Mechanistic and inhibition studies on isocitrate dehydrogenase 1 |
| title_full_unstemmed | Mechanistic and inhibition studies on isocitrate dehydrogenase 1 |
| title_short | Mechanistic and inhibition studies on isocitrate dehydrogenase 1 |
| title_sort | mechanistic and inhibition studies on isocitrate dehydrogenase 1 |
| work_keys_str_mv | AT lius mechanisticandinhibitionstudiesonisocitratedehydrogenase1 |