Estrogen receptor ligands. Part 10: Chromanes: old scaffolds for new SERAMs

Tan, Qiang; Blizzard, Timothy A.; Morgan, Jerry D.; Birzin, Elizabeth T.; Chan, Wanda; Yang, Yi Tien; Pai, Lee Yuh; Hayes, Edward C.; DaSilva, Carolyn; Warrier, Sudha; Yudkovitz, Joel B.; Wilkinson, Hilary A.; Sharma, Nandini; Fitzgerald, Paul J.; Li, Susan; Colwell, Lawrence F.; Fisher, John; Adamski, Sharon; Reszka, Alfred A.; Kimmel, Donald B.; DiNinno, Frank; Rohrer, Susan P.; Freedman, Leonard P.; Schaeffer, James M.; Hammond, Milton L.

doi:10.1016/j.bmcl.2005.01.046

Cited by 46 publications

(31 citation statements)

References 16 publications

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“…Achieving oral bioavailability has remained a key challenge in the design of ER downregulators and until now no oral estrogen receptor downregulators, other than GDC-0810 and RAD1901, have progressed into clinical trials, despite encouraging reports from others of preclinical activity in mouse xenograft models (16)(17)(18)(19)(20)(21). Here, we describe a chemically novel, nonsteroidal ERa antagonist and downregulator, AZD9496, that can be administered orally and links increased tumor growth inhibition to enhanced biomarker modulation compared with fulvestrant in a preclinical in vivo model of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive andESR1-Mutant Breast Tumors in Preclinical Models

et al. 2016

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Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERa, which is a potent and selective antagonist and downregulator of ERa in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity.Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERa protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER þ breast cells that could provide meaningful benefit to ER þ breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive andESR1-Mutant Breast Tumors in Preclinical Models

et al. 2016

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“…Numerous reviews of these two studies have been published Kong, Pike, and Hubbard, 2003;MuellerFahrnow and Egner, 1999; as have many further studies on the X-ray structures of SERMs, full antagonists and full agonists bound to the ERs Dykstra et al, 2007;Heldring et al, 2007;Kim et al, 2004;Renaud et al, 2003;Renaud et al, 2005;Tan et al, 2005;Vajdos et al, 2007). The same helix-12 clash has also been demonstrated for AR (Cantin et al, 2007) and GR (Schoch et al, 2010) in recent X-ray structure determination studies.…”

Section: Additional Examplesmentioning

confidence: 80%

Drug Design Approaches to Manipulate the Agonist-Antagonist Equilibrium in Steroid Receptors

Lusher¹,

Conti²,

Dokter³

et al. 2012

Steroids - Basic Science

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“…Numerous crystal structures of ERa complexed with various SERMs have revealed a conserved mode of binding, the primary features of which involve (1) a hydrogen-bond acceptor that serves to ''anchor'' the ligand in the ERa ligandbinding pocket via a polar interaction with Arg 394; (2) a nearly planar ''core'' structure typically composed of a biaryl heterocycle, analogous to the A-ring and B-ring of 17b-estradiol; (3) a ''pendant'' side chain emanating from the ''B-ring equivalent'' of the biaryl structure (analogous to the B-ring of estradiol); and (4) a second substituent (typically aromatic) that fills the remainder (''C-ring and D-ring'' equivalent) volume of the ligand-binding pocket. A variety of SERMs with biaryl core structures have been identified in recent years, including tetrahydroisoquinolines, benzothiophenes, chromanes, and dihydrobenzoxathiins (Brzozowski et al 1997;Renaud et al 2003Renaud et al , 2005Kim et al 2004;Blizzard et al 2005;Tan et al 2005). X-ray crystal structures of representatives of each of these scaffolds illustrate the generality of the Arg 394 H-bond ''anchor'' and planar, biaryl topology features of SERM recognition ( Fig.…”

Section: Discussionmentioning

confidence: 99%

The 2.0 Å crystal structure of the ERα ligand‐binding domain complexed with lasofoxifene

et al. 2007

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Lasofoxifene is a new and potent selective estrogen receptor modulator (SERM). The structural basis of its interaction with the estrogen receptor has been investigated by crystallographic analysis of its complex with the ligand-binding domain of estrogen receptor a at a resolution of 2.0 Å . As with other SERMs, lasofoxifene diverts the receptor from its agonist-bound conformation by displacing the C-terminal AF-2 helix into the site at which the LXXLL motif of coactivator proteins would otherwise be able to bind. Lasofoxifene achieves this effect by occupying the space normally filled by residue Leu 540, as well as by modulating the conformation of residues of helix 11 (His 524, Leu 525). A welldefined salt bridge between lasofoxifene and Asp 351 suggests that charge neutralization in this region of the receptor may explain the some of the antiestrogenic effects of lasofoxifene. The results suggest general features of ERa/SERM recognition, and add a new dimension to efforts to rationalize differences between the biological activity profiles exhibited by these important pharmacological agents.

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Estrogen receptor ligands. Part 10: Chromanes: old scaffolds for new SERAMs

Cited by 46 publications

References 16 publications

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive andESR1-Mutant Breast Tumors in Preclinical Models

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive andESR1-Mutant Breast Tumors in Preclinical Models

Drug Design Approaches to Manipulate the Agonist-Antagonist Equilibrium in Steroid Receptors

The 2.0 Å crystal structure of the ERα ligand‐binding domain complexed with lasofoxifene

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