Bispecific Estrogen Receptor a Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening

Disch Jeremy S.; Duffy Jennifer M.; Lee Esther C. Y.; Gikunju Diana; Chan Betty; Levin Benjamin; Monteiro Michael I; Talcott Sarah A.; Lau Anthony C.; Zhou Fei; Kozhushnyan Anton; Westlund Neil E.; Mullins Patrick B.; Yu Yan; von Rechenberg Moritz; Zhang Junyi; Arnautova Yelena A.; Liu Yanbin; Zhang Ying; McRiner Andrew J.; Keefe Anthony D.; Kohlmann Anna; Clark Matthew A.; Cuozzo John W.; Huguet Christelle; Arora Shilpi

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Bispecific Estrogen Receptor a Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening

机译：双特异性雌激素受体掺入使用DNA编码的化学文库筛选鉴定的新粘合剂的降解剂

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Bispecific degraders (PROTACs) of ER alpha are expected to be advantageous over current inhibitors of ER alpha signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening similar to 120 billion DNA-encoded molecules with ER alpha WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ER alpha competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ER alpha binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ER alpha, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.

机译：与目前用于治疗ER+乳腺癌的ER-α信号抑制剂（芳香化酶抑制剂/SERM/SERD）相比，ER-α的双特异性降解物（PROTAC）有望发挥优势。来自DNA编码化学库（DECL）筛选的信息提供了一种方法来识别新的PROTAC结合特征，作为连接子定位，结合元素直接从筛选中确定。在筛选了类似于1200亿DNA编码分子的ERαWT和3功能增益（GOF）突变体（含和不含雌二醇）以确定竞争性富集ERα的特征后，非DNA合成的小分子样本7表现出纳摩尔ERα结合、拮抗和降解。点击炔烃E3连接酶接合器面板上的化学合成，以及7种快速生成的ERα双特异性纳摩尔降解物的叠氮化物变体，在小鼠异种乳腺癌移植模型中，PROTACs 18和21抑制ER+MCF7肿瘤生长。这项研究验证了这种方法，可以通过最小优化从DECL筛选中识别新的双特异性降解剂线索。

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《Journal of Medicinal Chemistry》 |2021年第8期|共18页
作者
Disch Jeremy S.; Duffy Jennifer M.; Lee Esther C. Y.; Gikunju Diana; Chan Betty; Levin Benjamin; Monteiro Michael I; Talcott Sarah A.; Lau Anthony C.; Zhou Fei; Kozhushnyan Anton; Westlund Neil E.; Mullins Patrick B.; Yu Yan; von Rechenberg Moritz; Zhang Junyi; Arnautova Yelena A.; Liu Yanbin; Zhang Ying; McRiner Andrew J.; Keefe Anthony D.; Kohlmann Anna; Clark Matthew A.; Cuozzo John W.; Huguet Christelle; Arora Shilpi;
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X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

X Chem Inc Waltham MA 02453 USA;

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中图分类药学;
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Bispecific Estrogen Receptor a Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening

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