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TitleOral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models.
Journal, issue, pagesClin Cancer Res, Vol. 30, Issue 16, Page 3549-3563, Year 2024
Publish dateAug 15, 2024
AuthorsSheryl M Gough / John J Flanagan / Jessica Teh / Monica Andreoli / Emma Rousseau / Melissa Pannone / Mark Bookbinder / Ryan Willard / Kim Davenport / Elizabeth Bortolon / Gregory Cadelina / Debbie Gordon / Jennifer Pizzano / Jennifer Macaluso / Leofal Soto / John Corradi / Katherine Digianantonio / Ieva Drulyte / Alicia Morgan / Connor Quinn / Miklós Békés / Caterina Ferraro / Xin Chen / Gan Wang / Hanqing Dong / Jing Wang / David R Langley / John Houston / Richard Gedrich / Ian C Taylor /
PubMed AbstractPURPOSE: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such ...PURPOSE: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed.
EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI).
RESULTS: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib.
CONCLUSIONS: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.
External linksClin Cancer Res / PubMed:38819400 / PubMed Central
MethodsEM (single particle)
Resolution3.7 Å
Structure data

EMDB-40261: DDB1/CRBN in complex with ARV-471 and the ER ligand-binding domain
Method: EM (single particle) / Resolution: 3.7 Å

Source
  • Homo sapiens (human)

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