Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha
| Autor: | Tommy Lai, Maia Vinogradova, Jun Liang, Yu Zhong, Birong Zhang, Jae H. Chang, Xiaojing Wang, Yingqing Ran, Hai Chen, Deepak Sampath, Robert A. Blake, Ellen Ingalla, Jerome C. Nwachukwu, James R. Kiefer, Daniel F. Ortwine, Jiangpeng Liao, Tracy Kleinheinz, Amy Sambrone, Xiaoping Zheng, Kendall W. Nettles, Steven J. Hartman, Vidhi Mody, Michelle Nannini |
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| Rok vydání: | 2018 |
| Předmět: |
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Molecular Stereochemistry Protein Conformation Clinical Biochemistry Azetidine Pharmaceutical Science Estrogen receptor Antineoplastic Agents 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Side chain Humans Benzopyrans Nuclear protein Molecular Biology Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Estrogen Receptor alpha 0104 chemical sciences 3. Good health 010404 medicinal & biomolecular chemistry Selective estrogen receptor modulator MCF-7 Cells Molecular Medicine Signal transduction Enantiomer Crystallization Estrogen receptor alpha Signal Transduction |
| Zdroj: | Bioorganicmedicinal chemistry letters. 29(7) |
| ISSN: | 1464-3405 |
| Popis: | Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+ breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays. |
| Databáze: | OpenAIRE |
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