Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells

Min, Jian; Guillen, Valeria Sanabria; Sharma, Abhishek; Zhao, Yuechao; Ziegler, Yvonne; Gong, Ping; Mayne, Christopher G.; Srinivasan, Sathish; Kim, Sung Hoon; Carlson, Kathryn E.; Nettles, K.W.; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.

doi:10.1021/acs.jmedchem.7b00585

Cited by 29 publications

(23 citation statements)

References 60 publications

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“…Thus, combining indirect and direct antagonism produced a series of compounds all having full antiproliferative efficacy, including those with benzyl side chains. These findings differ markedly from previous work by us 20 and others 5,21-divergent outcomes in terms of efficacy, and they highlight the more restricted chemical and structural requirements needed for good single-mechanism inhibition of ERα activity 20,24,25 .…”

Section: Dual-mechanism Inhibitor Designcontrasting

confidence: 96%

Dual mechanism estrogen receptor inhibitors

Min

Nwachukwu

Srinivasan

et al. 2020

Preprint

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AbstractCurrent antiestrogen therapies for estrogen receptor alpha (ERa)-positive breast cancers work only by direct antagonism, using a single side chain that extends outward from the ligand core to disrupt the transcriptional coactivator-binding site via a direct steric interaction that requires precise chemical targeting. Here, we present a new class of antiestrogens with a 7-oxa-bicyclo[2.2.1]heptene sulfonamide core that combines direct antagonism with indirect antagonism, to also modulate the coactivator-binding site indirectly. These dual-mechanism ER inhibitors (DMERIs) fully antagonized the proliferation of breast cancer cells, including tamoxifen-resistant models, irrespective of their side chain structure and substitution site. These inhibitors displayed an ensemble of binding modes and associated receptor conformational sub-states that drive their unique properties, verified with solution structural probes. Dualmechanism inhibitors of ERα thus represent an approach to therapeutic targeting with robust efficacy, novel binding modes and associated structural perturbations, and greater tolerance for chemical variety in ligand design.

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Section: Dual-mechanism Inhibitor Designcontrasting

confidence: 96%

Dual mechanism estrogen receptor inhibitors

Min

Nwachukwu

Srinivasan

et al. 2020

Preprint

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“…The mutants examined, Y537S and D538G, are the two most commonly occurring mutant ERα’s in humans with therapy-resistant breast cancers. The three antiestrogens have an adamantyl core and were selected through structure-activity relationship studies on breast cancer cells with wild type ER(20). Hence, the current studies are the first to examine their effects on cells and tumors with growth driven by constitutively active ERs.…”

Section: Resultsmentioning

confidence: 99%

“…AZD9496 was from MedChemExpress. The preparations of the antiestrogens K-07, K-09 and K-62 have been reported (20). MCF7 and T47D cells from the ATCC were maintained and cultured as described (21,22).…”

Section: Methodsmentioning

confidence: 99%

Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

et al. 2017

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Many ERα-positive breast cancers develop resistance to endocrine therapy via mutation of estrogen receptors (ER) whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ER, we describe here our development and characterization of three chemically novel AE that effectively suppress proliferation of breast cancer cells and tumors. Our AE are effective against wild type and Y537S and D538G ER, the two most commonly occurring constitutively active ER. The 3 new AE suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared to WT ER, mutants exhibited ~10 to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER-containing MCF7 and T47D cells revealed that AE responses were compound, cell-type and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER-expressing tumor xenografts in NOD/SCID-gamma mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ER to different AE and make clear the value of having a toolkit of AE for treatment of endocrine therapy-resistant tumors driven by different constitutively active ER.

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“…In particular, the carboxylic OH was replaced with alkoxy or N-alkyl amido groups having terminal OH or NH 2 . [60] The bisphenolic adamantyl core was expected to provide high binding affinity (3-fold higher than that of E2) and avoids stereochemical issues due to its lack of geometric isomerism (present in GW5630 and GCD-0810) and chiral centers (present in AZD-9496). The polar terminal groups on acrylic acid derivatives were hypothesized to replace the structural water which is known to mediate the interaction between the acrylic acid side chain and the Nterminus of h12.…”

Section: Acrylic Acid Derivativesmentioning

confidence: 99%

The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs)

Wang

Sharma

2020

ChemMedChem

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Research Institute in 1994, have been reported as promising orally bioavailable SERDs. Some of these compounds are currently in clinical trials, while various other structurally novel SERDs have also been reported by pharma as well as academic research groups. This review provides a critical analysis of the recent developments in orally available SERDs, with a focus on the structure-activity relationships, binding interactions and pharmacokinetic properties of these compounds [a

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Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells

Cited by 29 publications

References 60 publications

Dual mechanism estrogen receptor inhibitors

Dual mechanism estrogen receptor inhibitors

Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs)

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