What question did this study set out to answer?

To design and evaluate novel C6-substituted androsta-1,4-diene-3,17-dione aromatase inhibitors based on the crystal structure of human placental aromatase.

September 5, 2012Journal of Medicinal ChemistryOpen Access

Novel Aromatase Inhibitors by Structure-Guided Design

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Authors

DGDebashis GhoshRoyal Free London NHS Foundation Trust JLJessica LoSUNY Upstate Medical University DMDaniel MortonSecond Genome (United States)

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Implication

Preclinical study demonstrates potent antiproliferative activity of novel aromatase inhibitors in breast cancer cells, indicating improved therapeutic efficacy over exemestane.

Key Points

To design and evaluate novel C6-substituted androsta-1,4-diene-3,17-dione aromatase inhibitors based on the crystal structure of human placental aromatase.
Designed novel C6-substituted 2-alkynyloxy derivatives targeting an unoccupied access channel identified in human placental aromatase crystal structures.
Assayed enzyme inhibition (IC50) in purified placental aromatase and measured antiproliferative effects (EC50) in estrogen-dependent MCF-7 breast cancer cell cultures.
Determined high-resolution X-ray crystal structures of aromatase in complex with two potent inhibitor candidates to analyze binding interactions.
Multiple C6-substituted 2-alkynyloxy compounds inhibited purified placental aromatase with IC50 values within the nanomolar range.
Top compounds demonstrated antiproliferative potency with EC50 values below 1 nM in MCF-7 breast cancer cells, exceeding the potency of exemestane.
X-ray crystal structures confirmed that the novel C6 side groups protrude into the enzyme's access channel opening, verifying the structure-activity relationship.

Cite This Study

Ghosh et al. (2012) studied this question.

synapsesocial.com/papers/69dce5522e182f147e1335a3 https://doi.org/10.1021/jm300930n

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Implication

Preclinical study demonstrates potent antiproliferative activity of novel aromatase inhibitors in breast cancer cells, indicating improved therapeutic efficacy over exemestane.

Novel Aromatase Inhibitors by Structure-Guided Design

Discussion

Member takes

Implication

Key Points

Cite This Study

Novel Aromatase Inhibitors by Structure-Guided Design

Discussion

Member takes

Implication

Key Points

Cite This Study

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