Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927

Labadie, Sharada S.; Li, Jun; Blake, Robert A.; Chang, Jae Hoon; Goodacre, Simon; Hartman, Steven J.; Liang, Weiling; Kiefer, James R.; Kleinheinz, Tracy; Lai, Tommy; Liao, Jiangpeng; Ortwine, Daniel F.; Mody, Vidhi; Ray, Nicholas C.; Roussel, Fabien; Vinogradova, Maia; Yeap, Siew Kuen; Zhang, Birong; Zheng, Xiaoping; Zbieg, Jason R.; Liang, Jun; Wang, Xiaojing

doi:10.1016/j.bmcl.2019.07.013

Cited by 13 publications

(18 citation statements)

References 19 publications

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“…The authors have not made it clear if this is due to the nature of the compound or the quality of the crystal itself. Apart from that, GDC-0927 forms hydrogen bonds on one side with Glu353, Arg394 and Leu387 and on the other side with His524 along with a hydrogen bond interaction between Asp351 and the azetidine nitrogen in the side chain ( Figure 10b) (pdb entry 6PFM) [42,270]. Elacestrant/RAD1901 is a SERM/SERD hybrid substance developed by Hattersley et al for Radius Pharmaceuticals in 2015, and is currently in Phase III trial aiming to compare its safety and efficacy to the standard endocrine therapy in combination with fulvestrant or AI in advanced ERα+/HER-setting [262].…”

Section: Fulvestrantmentioning

confidence: 99%

“…In Phase I trials, it was determined that the compound was safe and tolerable in metastatic ERα+/HER- BCa in post-menopausal women including patients harboring ESR1 mutations [ 269 ]. The structure of GDC-0927 in complex with ERα has been resolved but the H12 seems disordered in its packing to the rest of the ER as seen in Figure 10 a using MOE package [ 42 , 270 ]. The authors have not made it clear if this is due to the nature of the compound or the quality of the crystal itself.…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

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Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

Bafna

Ban

Rennie

et al. 2020

IJMS

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Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery.

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Section: Fulvestrantmentioning

confidence: 99%

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

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Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

Bafna

Ban

Rennie

et al. 2020

IJMS

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“…[77] More recent preclinical evidence has revealed the high clearance and low oral bioavailability of GDC-0927 112, which limited human dose-escalation studies, likely due to the presence of two electron-rich phenols in the molecule. [78] Previous attempts at replacing the 3'-OH with a fluorine atom to improve ADMET properties resulted in improved microsomal stability at the expense of degradation potency (tenfold loss). [75] With the aim to attenuate the metabolic liabilities of phenolcontaining molecules, Wang and co-workers tested a series of phenol bioisosteres.…”

Section: Chromene Derivativesmentioning

confidence: 99%

“…[75] With the aim to attenuate the metabolic liabilities of phenolcontaining molecules, Wang and co-workers tested a series of phenol bioisosteres. [78] In general, modifying the D-ring with heterocycles (Table 12, 113-115), cycloalkyl (116-117) or alkyl (118) moieties failed to improve the metabolic stability while maintaining potency. A-ring phenol replacements and bioisosteres were not tolerated either (Table 13, 119-123).…”

Section: Chromene 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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Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

Ding

Jiang

Zhang

et al. 2022

Nat. Prod. Bioprospect.

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Structural derivatization of natural products has been a continuing and irreplaceable source of novel drug leads. Natural phenols are a broad category of natural products with wide pharmacological activity and have offered plenty of clinical drugs. However, the structural complexity and wide variety of natural phenols leads to the difficulty of structural derivatization. Skeleton analysis indicated most types of natural phenols can be structured by the combination and extension of three common fragments containing phenol, phenylpropanoid and benzoyl. Based on these fragments, the derivatization strategies of natural phenols were unified and comprehensively analyzed in this review. In addition to classical methods, advanced strategies with high selectivity, efficiency and practicality were emphasized. Total synthesis strategies of typical fragments such as stilbenes, chalcones and flavonoids were also covered and analyzed as the supplementary for supporting the diversity-oriented derivatization of natural phenols.

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Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927

Cited by 13 publications

References 19 publications

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

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

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

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