Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD)

Lu, Jianyu; Chan, Chi-Chung; Sun, Deheng; Hu, Guoping; He, Huijun; Li, Jian; Dong, Jiaqiang; Li, Kai; Shen, Liang; Hu, Lihong; Gu, Qing; Chen, Shuhui; Wang, Tielin; Gong, Ting; Tang, Wei; Li, Xiaoting; Zhu, Xiao‐Qing; Xu, Zhuo; Zhu, Yingjie; Xia, Yuanfeng; Huang, Yuanyuan; Zhu, Yusong; Liu, Zhenteng; Ding, Charles Z.

doi:10.1016/j.bmcl.2022.128734

Cited by 10 publications

(13 citation statements)

References 10 publications

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“…Compound 9.1 was coupled with 2-chloro-4-fluoro-1-iodobenzene under Suzuki conditions followed by ester hydrolysis to give the corresponding acid 9.3 . Compound 9.3 underwent chlorination at the indole C-3 position to provide the desired compound LX-039 …”

Section: Oral Serds With An Acrylic Acid Side Chainmentioning

confidence: 97%

“…Ding et al recently reported a novel indole-based oral SERD LX-039 from a novel ER-binding motif 9a . LX-039 ( 9 , Figure ), with an indole C-3 chlorine atom, improved more than 5-fold the antiproliferative potency against the MCF-7 cell line and almost 20-fold the ER degradation potency (EC 50 ) compared to compound 9a in MCF-7 cells.…”

Section: Oral Serds With An Acrylic Acid Side Chainmentioning

confidence: 99%

“…The body weight changes among drug-dosed groups tracked well with vehicle control animals. In a mouse tamoxifen-resistant MCF-7 xenograft model study, LX-039 significantly suppressed tumor growth from 30 to 200 mg/kg dose, with TGI at 200 mg/kg reaching 91% …”

Section: Oral Serds With An Acrylic Acid Side Chainmentioning

confidence: 99%

“…In all species evaluated, bioavailability ranged from F = 55% to 60% (Table ). Taken together, LX-039 exhibited excellent PK, low CL, high C max , and oral exposure supporting its progression into clinical trials …”

Section: Oral Serds With An Acrylic Acid Side Chainmentioning

confidence: 99%

“…118 In a mouse MCF- suppressed tumor growth from 30 to 200 mg/kg dose, with TGI at 200 mg/kg reaching 91%. 118 Synthesis of Compound LX-039 (9). LX-039 was synthesized from commercially available compound 9.1 in three steps (Scheme 9; clinical trial data are in Table 17).…”

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confidence: 99%

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Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and Challenges

et al. 2023

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Estrogen receptor alpha (ERα) is a well-established therapeutic target for the treatment of ER-positive (ER+) breast cancers. Despite the tremendous successes achieved with tamoxifen, a selective ER modulator, and aromatase inhibitors (AIs), resistance to these therapies is a major clinical problem. Therefore, induced protein degradation and covalent inhibition have been pursued as new therapeutic approaches to target ERα. This Perspective summarizes recent progress in the discovery and development of oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), and proteolysis targeting chimera (PROTAC) ER degraders. We focus on those compounds which have been advanced into clinical development.

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Section: Oral Serds With An Acrylic Acid Side Chainmentioning

confidence: 97%

Section: Oral Serds With An Acrylic Acid Side Chainmentioning

confidence: 99%

Section: Oral Serds With An Acrylic Acid Side Chainmentioning

confidence: 99%

Section: Oral Serds With An Acrylic Acid Side Chainmentioning

confidence: 99%

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confidence: 99%

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Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and Challenges

et al. 2023

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The anti‐breast cancer potential of indole/isatin hybrids

Wang,

Huang,

Yuan

et al. 2023

Archiv der Pharmazie

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Breast cancer (BC) is one of the most prevalent malignancies and the major contributor to cancer mortality in women globally, with a high degree of heterogeneity and a dismal prognosis. As drug resistance is responsible for most BC fatalities and advanced BC is currently considered incurable, finding innovative anti‐BC chemotherapeutics is urgently required. Indole and its analog isatin (indole‐1H‐2,3‐dione) are prominent pharmacophores in the development of novel medications, and their derivatives exhibit strong anticancer activities, also against BC. In particular, indole/isatin hybrids exhibit significant potency against BC including multidrug‐resistant forms and excellent selectivity by influencing a variety of biological targets associated with the disease, supplying helpful building blocks for the identification of potential new BC treatment options. This review includes articles from 2020 to the present and provides insights into the in vitro and in vivo anti‐BC potential, molecular mechanisms, and structure–activity relationships (SARs) of indole/isatin hybrids that may be helpful in the development of innovative anti‐BC chemotherapeutics.

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Selenium Analogue of LSZ102 as a Highly Potent ER‐α Binder

Paegle

Arsenyan

2023

Eur J Org Chem

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Nowadays, selective estrogen receptor modulators (SERMs) and downregulators (SERDs) are used as the first-line medical treatment for estrogen receptor positive (ER +) tumors. Herein we report synthesis, ER-α binding activity, and cytotoxicity of LSZ102 selenium analogues 11 and 28. TR-FRET competitive ERα binding experiments and cytotoxicity assays have shown that the selenium analogues exhibit closely related activity to LSZ102. Furthermore, the prepared selenium analogues are not toxic in rat cardiomyoblasts (H9C2), indicating that substituted benzo[b]selenophene is a prospective scaffold for the development of ER-α modulators and downregulators for the treatment of ER + cancers.

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Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD)

Cited by 10 publications

References 10 publications

Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and Challenges

Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and Challenges

The anti‐breast cancer potential of indole/isatin hybrids

Selenium Analogue of LSZ102 as a Highly Potent ER‐α Binder

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