AI Article Synopsis
- * Docking analyses revealed that elacestrant's structure could be rapidly metabolized by the CYP3A4 enzyme due to its tetrahydronaphthalene scaffold interacting closely with the heme iron center of cytochrome P450s.
- * A modified compound, B16, showed significant degradation of the estrogen receptor alpha (ERα) at 5 μM, but did not inhibit cell growth, suggesting its potential use as a probe for studying ER status in ER-positive breast cancer cells.
Article Abstract
Elacestrant, the first oral selective estrogen receptor degrader (SERD), has been approved for ER positive breast cancer in 2023. Recent study showed that elacestrant has moderate pharmacokinetic property and the oral bioavailability is 11 %. In this study, we have performed docking analyses of elacestrant with different cytochrome P450 isoforms. The results indicated that tetrahydronaphthalene scaffold of elacestrant located closely to Heme iron center of P450s and might undergo rapid metabolism by CYP3A4. Therefore, we have changed the tertiary carbon atom to nitrogen atom of the scaffold to attenuate the metabolic effect. The most interesting finding is that compound B16 exhibited significant degradation of ERα at 5 μM but didn't show antiproliferative activity at high concentrations in MCF-7 and T47D cells. Compound B16 may serve as an ER probe to investigate ER status in ER positive breast cancer cells.
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| http://dx.doi.org/10.1016/j.ejmech.2024.116897 | DOI Listing |
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