Discovery of a Selective and Orally Bioavailable RET Degrader with Effectiveness in Various Mutations
The rearranged during transfection (RET) mutation such as the G810C mutation has significantly restricted the clinical application of selective RET inhibitors in the treatment of RET-driven cancers. This study designed and evaluated RET proteolysis targeting chimeras (PROTACs) based on selpercatinib...
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| Veröffentlicht in: | Journal of medicinal chemistry 2025-01 |
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| container_title | Journal of medicinal chemistry |
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| creator | Hualong, Mo Liu, JieYing Yin, Ting Cao, XuXu Su, ZhengXi Zhao, Deng-Gao Ma, Yan-Yan |
| description | The rearranged during transfection (RET) mutation such as the G810C mutation has significantly restricted the clinical application of selective RET inhibitors in the treatment of RET-driven cancers. This study designed and evaluated RET proteolysis targeting chimeras (PROTACs) based on selpercatinib (LOXO-292), identifying
as a potent and selective RET PROTAC.
effectively inhibited the proliferation of BaF3 cells with various RET mutations, showing IC
values of 2.4 to 6.5 nM. It selectively induced degradation of the RET
mutation via the ubiquitin-proteasome system, with a DC
(concentration causing 50% of protein degradation) value of 11.7 nM. Additionally,
exhibited oral bioavailability and superior antitumor effects compared to LOXO-292 in a Ba/F3-KIF5B-RET
xenograft mouse model. These results suggested that
is a promising candidate for treating RET-driven cancers. |
| doi_str_mv | 10.1021/acs.jmedchem.4c01889 |
| format | Article |
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as a potent and selective RET PROTAC.
effectively inhibited the proliferation of BaF3 cells with various RET mutations, showing IC
values of 2.4 to 6.5 nM. It selectively induced degradation of the RET
mutation via the ubiquitin-proteasome system, with a DC
(concentration causing 50% of protein degradation) value of 11.7 nM. Additionally,
exhibited oral bioavailability and superior antitumor effects compared to LOXO-292 in a Ba/F3-KIF5B-RET
xenograft mouse model. These results suggested that
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as a potent and selective RET PROTAC.
effectively inhibited the proliferation of BaF3 cells with various RET mutations, showing IC
values of 2.4 to 6.5 nM. It selectively induced degradation of the RET
mutation via the ubiquitin-proteasome system, with a DC
(concentration causing 50% of protein degradation) value of 11.7 nM. Additionally,
exhibited oral bioavailability and superior antitumor effects compared to LOXO-292 in a Ba/F3-KIF5B-RET
xenograft mouse model. These results suggested that
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as a potent and selective RET PROTAC.
effectively inhibited the proliferation of BaF3 cells with various RET mutations, showing IC
values of 2.4 to 6.5 nM. It selectively induced degradation of the RET
mutation via the ubiquitin-proteasome system, with a DC
(concentration causing 50% of protein degradation) value of 11.7 nM. Additionally,
exhibited oral bioavailability and superior antitumor effects compared to LOXO-292 in a Ba/F3-KIF5B-RET
xenograft mouse model. These results suggested that
is a promising candidate for treating RET-driven cancers.</abstract><cop>United States</cop><pmid>39772547</pmid><doi>10.1021/acs.jmedchem.4c01889</doi><orcidid>https://orcid.org/0000-0003-1143-4106</orcidid><orcidid>https://orcid.org/0000-0002-8639-712X</orcidid></addata></record> |
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| title | Discovery of a Selective and Orally Bioavailable RET Degrader with Effectiveness in Various Mutations |
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