Vepdegestrant

Vepdegestrant

CAS 2229711-08-2

MW 723.9 g/mol, C45H49N5O4

• (S)-3-(5-(4-((1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
• (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione
• (2(1)R,2(2)S,8(3)S)-2-hydroxy-2(1),2(2),2(3),2-tetrahydro-7(5,2)-isoindola-6(1,4)-piperazina-4(1,4),8(3)-dipiperidina-2(2,1)-naphthalena-1(1),3(1,4)-dibenzenaoctaphane-7(1),8(2),8(7(3)H)-trione
• 2,6-Piperidinedione, 3-(1,3-dihydro-1-oxo-5-(4-((1-(4-((1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthalenyl)phenyl)-4-piperidinyl)methyl)-1-piperazinyl)-2H-isoindol-2-yl)-, (3S)-

(3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione

5/1/2026, FDA 2026, APROVALS 2026, Veppanu, ARV 471, WC1U3R1YMI, PF 07850327

To treat estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy

On May 1, 2026, the FDA approved vepdegestrant (Veppanu), a first-in-class oral PROTAC estrogen receptor (ER) degrader developed by Arvinas and Pfizer, for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer who have progressed on endocrine therapy. It demonstrated significant progression-free survival (PFS) improvements compared to fulvestrant.

Key Details About Vepdegestrant (Veppanu):

• Mechanism of Action: As an oral PROTAC (Proteolysis-Targeting Chimera), vepdegestrant targets the estrogen receptor for degradation, designed to be more effective than traditional endocrine therapies, particularly in ESR1-mutated tumors.
• Approved Indication: For treating adults with ER+/HER2-, ESR1-mutated advanced/metastatic breast cancer (detected by Guardant360 CDx) after at least one line of endocrine therapy.
• Dosage: The recommended dose is 200 mg taken orally once daily with food.
• Clinical Efficacy (VERITAC-2): In trials, vepdegestrant showed a significantly longer PFS compared to intramuscular fulvestrant.
• Side Effects & Risks: Common side effects include decreased white blood cell counts, increased liver function tests, muscle/bone pain, fatigue, and nausea. Warnings include embryo-fetal toxicity and QTc interval prolongation (heart rhythm issues).
• Companion Diagnostic: Guardant360 CDx was approved alongside the drug to identify patients with ESR1 mutations

Vepdegestrant (developmental code name ARV-471) is an investigational oral proteolysis-targeting chimera (PROTAC) compound that targets the estrogen receptor for protein degradation. It is being developed for the treatment of estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer by Arvinas and Pfizer.^[1][2][3]

Mechanism of action

Vepdegestrant is designed as a PROTAC that recruits the ubiquitin-proteasome system to target the estrogen receptor for degradation.^[4] The compound contains both an E3 ubiquitin ligase-binding moiety and an estrogen receptor-binding domain, intended to bring these proteins into proximity to trigger ubiquitination and subsequent proteasomal degradation of the ER protein.^[5] In laboratory studies, vepdegestrant demonstrated ER degradation in ER-positive breast cancer cell lines with reported DC50 values of approximately 1-2 nM.^[6]

Vepdegestrant is an orally available hetero-bifunctional molecule and selective estrogen receptor (ER) alpha-targeted protein degrader, using the proteolysis targeting chimera (PROTAC) technology, with potential antineoplastic activity. Vepdegestrant is composed of an ER alpha ligand attached to an E3 ligase recognition moiety. Upon oral administration,vepdegestrant targets and binds to the ER ligand binding domain on ER alpha. E3 ligase is recruited to the ER by the E3 ligase recognition moiety and ER alpha is tagged by ubiquitin. This causes ubiquitination and degradation of ER alpha by the proteasome. This decreases ER alpha protein levels, decreases the expression of ER alpha-target genes and halts ER-mediated signaling. This results in an inhibition of proliferation in ER alpha-overexpressing tumor cells. In addition, the degradation of the ER alpha protein releases the ARV-471 and can bind to additional ER alpha target proteins. ER alpha is overexpressed in a variety of cancers and plays a key role in cancer cell proliferation.

SYN

https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/slct.202405939

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US319556813&_cid=P11-MOP5B0-05496-1

Step 11: Preparation of 3-[5-[4-[[1-[4-[(1R, 2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound (I-b))

To a solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione hydrochloride (319 mg, 0.87 mmol, prepared in Step 17 described for Exemplary Compound 62) in methanol (4 mL) and dichloromethane (4 mL) was added sodium acetate (120 mg, 1.46 mmol, 2 eq). The mixture was stirred at 20° C. for 0.5 h, then to the mixture was added 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (300 mg, 0.73 mmol, 1 eq) and sodium cyanoborohydride (137 mg, 2.19 mmol, 3 eq). The mixture was stirred at 20° C. for 12 h. LC-MS showed the starting material was consumed completely and one main peak with desired MW was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex luna C ₁₈ column, 250×50 mm, 10 um; mobile phase: [water (0.05% HCl)-acetonitrile]; B %: acetonitrile 10%-40% in 30 min). The desired compound 3-[5-[4-[[1-[4-[(1R, 2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (288.4 mg, 0.37 mmol, 51% yield) was obtained as a white solid of hydrochloride salt. LC-MS (ESI) m/z: 724.4 [M+1] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 10.97 (s, 1H), 10.83 (s, 0.9H, HCl), 7.60 (d, J=8.5 Hz, 1H), 7.40 (br s, 2H), 7.22-7.11 (m, 5H), 6.83 (d, J=6.0 Hz, 2H), 6.69-6.63 (m, 2H), 6.58-6.47 (m, 3H), 5.07 (dd, J=5.2, 13.2 Hz, 1H), 4.41-4.30 (m, 2H), 4.28-4.21 (m, 1H), 4.00 (d, J=12.7 Hz, 2H), 3.61 (d, J=11.0 Hz, 2H), 3.54-3.36 (m, 6H), 3.16 (br s, 4H), 3.06-2.84 (m, 3H), 2.76-2.53 (m, 1H), 2.43-2.33 (m, 1H), 2.27 (br s, 1H), 2.16-2.04 (m, 3H), 2.02-1.69 (m, 5H).

Synthesis of (3S)-3-[5-[4-[[1-[4-[(1R, 2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound (I-c))

To a mixture of (3 S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (1.30 g, 3.47 mmol, 1 eq, benzene sulfonate) in dichloromethane (8 mL) and methanol (32 mL) was added sodium acetate (854 mg, 10.41 mmol, 3 eq) in one portion at 20° C. The mixture was stirred at 20° C. for 10 minutes. Then 1-[4-[(1R, 2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl] piperidine-4-carbaldehyde (1 g, 2.43 mmol, 0.7 eq, prepared as described above in the synthesis of Compound (I-b)) was added. The mixture was stirred at 20° C. for 10 minutes. After that, acetic acid (0.2 mL) and sodium cyanoborohydride (436 mg, 6.94 mmol, 2 eq) was added in one portion. The mixture was stirred at 20° C. for 40 minutes. The mixture was concentrated in vacuum, and 50 mL of tetrahydrofuran and 20 mL of water were added. The mixture was stirred for 20 minutes. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8-9. The aqueous phase was extracted with ethyl acetate and tetrahydrofuran (v:v=2:1, 60 mL×3). The combined organic phase was washed with brine (60 mL×1), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative reverse phase HPLC (column: Phenomenex luna C18 250×50 mm, 10 micron; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 20%-50% in 30 min). The product (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl] piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (964 mg, 1.23 mmol, 35% yield, 98% purity, formate) was obtained as a white solid of formic acid salt after lyophilization. Chiral purity was analyzed by chiral SFC (Chiralcel OJ-3 50×4.6 mm, 3 micron; mobile phase: 50% ethanol (0.05% DEA) in CO 2; flow rate: 3 mL/min, wavelength: 220 nm) and observed t p=2.89 min with de over 95%. [α D=−267.5 (c=0.2 in DMF, 25° C.). LC-MS (ESI) m/z: 724.2 [M+1] +. 1H NMR (400 MHz, DMSO-d 6) δ 10.94 (s, 1H), 8.16 (s, 1H, formate), 7.51 (d, J=8.8 Hz, 1H), 7.21-6.98 (m, 5H), 6.83 (d, J=6.4 Hz, 2H), 6.68-6.57 (m, 2H), 6.56-6.44 (m, 3H), 6.20 (d, J=8.8 Hz, 2H), 5.04 (dd, J=5.2, 13.2 Hz, 1H), 4.32 (d, J=16.8 Hz, 1H), 4.19 (d, J=17.2 Hz, 1H), 4.12 (d, J=4.8 Hz, 1H), 3.51 (br d, J=10.0 Hz, 4H), 3.27 (br s, 8H), 3.03-2.82 (m, 3H), 2.63-2.54 (m, 1H), 2.43-2.28 (m, 2H), 2.19 (d, J=6.8 Hz, 2H), 2.15-2.02 (m, 1H), 2.01-1.89 (m, 1H), 1.83-1.51 (m, 4H), 1.28-1.04 (m, 2H).

1H-NMR of the free non-salt form: (400 MHz, DMSO-d 6) δ 10.93 (s, 1H), 9.09 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.18-7.09 (m, 3H), 7.08-7.02 (m, 2H), 6.83 (d, J=6.4 Hz, 2H), 6.64 (d, J=8.4 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.53 (d, J=8.8 Hz, 2H), 6.48 (dd, J=2.4, 8.4 Hz, 1H), 6.20 (d, J=8.8 Hz, 2H), 5.04 (dd, J=5.2, 13.2 Hz, 1H), 4.39-4.27 (m, 1H), 4.24-4.15 (m, 1H), 4.12 (d, J=4.8 Hz, 1H), 3.51 (d, J=9.6 Hz, 2H), 3.29-3.24 (m, 5H), 3.03-2.83 (m, 3H), 2.62-2.54 (m, 4H), 2.52 (s, 3H), 2.41-2.36 (m, 1H), 2.19 (d, J=7.2 Hz, 2H), 2.15-2.08 (m, 1H), 2.00-1.89 (m, 1H), 1.81-1.58 (m, 4H), 1.22-1.06 (m, 2H).

PAT

• Tetralin and tetrahydroisoquinoline derivatives as estrogen receptor degradersPublication Number: CN-118834201-APriority Date: 2016-12-01
• Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degradersPublication Number: EP-3689868-B1Priority Date: 2016-12-01Grant Date: 2023-09-27
• Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degradersPublication Number: US-10647698-B2Priority Date: 2016-12-01Grant Date: 2020-05-12
• Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degradersPublication Number: US-2025320195-A1Priority Date: 2016-12-01
• Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degradersPublication Number: US-10899742-B1Priority Date: 2016-12-01Grant Date: 2021-01-26
• Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degradersPublication Number: US-11104666-B2Priority Date: 2016-12-01Grant Date: 2021-08-31
• Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degradersPublication Number: US-12172981-B2Priority Date: 2016-12-01Grant Date: 2024-12-24

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References

References

1.  Iwata, H.; Naito, Y.; Hattori, M.; Yoshimura, A.; Yonemori, K.; Aizawa, M.; et al. (November 2023). “58P Safety and pharmacokinetics (PK) of vepdegestrant in Japanese patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Results from a Japanese phase I study”. Annals of Oncology. 34: S1488–S1489. doi:10.1016/j.annonc.2023.10.193. S2CID 265657144.
2.  Iwata, H.; Hamilton, E.P.; Ma, C.X.; De Laurentiis, M.; Hurvitz, S.A.; Wander, S.A.; et al. (November 2023). “73TiP Global phase III studies evaluating vepdegestrant in estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: VERITAC-2 and VERITAC-3”. Annals of Oncology. 34: S1493. doi:10.1016/j.annonc.2023.10.207. S2CID 265654990.
3.  “Arvinas, Pfizer reworking partnership on ‘Protac’ cancer drug | BioPharma Dive”. www.biopharmadive.com. Retrieved 17 September 2025.
4.  “Estrogen Receptor”. Arvinas. Retrieved 17 September 2025.
5.  Sakamoto, Kathryn M.; Kim, Kwon B.; Kumagai, Ayumu; Mercurio, Frank; Crews, Craig M.; Deshaies, Raymond J. (18 January 2022). “PROTAC targeted protein degraders: the past is prologue”. Nature Reviews Drug Discovery. 21 (3): 181–200. doi:10.1038/s41573-021-00371-6. PMC 8765495. PMID 35046570.
6.  “Vepdegestrant (ARV-471) PROTAC ER Degrader”. MedChemExpress. Retrieved 17 September 2025.
7.  Hamilton, Erika P.; Ma, Cynthia; De Laurentiis, Michelino; Iwata, Hiroji; Hurvitz, Sara A.; Wander, Seth A.; et al. (2024). “VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer”. Future Oncology (London, England). 20 (32): 2447–2455. doi:10.1080/14796694.2024.2377530. ISSN 1744-8301. PMC 11524203. PMID 39072356.
8.  “A Study to Compare the Efficacy and Safety of Vepdegestrant (ARV-471) Versus Fulvestrant in Participants With Estrogen Receptor-positive, HER2-negative Advanced Breast Cancer (VERITAC-2)”. ClinicalTrials.gov. 30 June 2025. Retrieved 17 September 2025.
9.  “Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial”. Arvinas. Retrieved 17 September 2025.
10.  “VERITAC-2 Trial Shows Vepdegestrant Significantly Improves Survival in ESR1-Mutant Breast Cancer”. Applied Clinical Trials Online. 24 March 2025. Retrieved 17 September 2025.
11.  “Arvinas Announces Results from the VERITAC-2 Trial Selected as Late-Breaking Oral Presentation at the 2025 ASCO Annual Meeting”. Arvinas. 23 April 2025. Retrieved 17 September 2025.
12.  Gough, Sheryl M.; Flanagan, John J.; Teh, Jimmy (15 August 2024). “Oral 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”. Clinical Cancer Research. 30 (16): 3549–3562. doi:10.1158/1078-0432.CCR-23-3465. PMC 11325148. PMID 38819400.
13.  “FDA Grants Fast Track Status to Vepdegestrant for ER+/HER2– Metastatic Breast Cancer”. Oncology Live. 6 February 2024. Retrieved 17 September 2025.
14.  “Vepdegestrant Gains FDA Fast Track Designation in ER+/HER2- Breast Cancer”. Targeted Oncology. 6 February 2024. Retrieved 17 September 2025.
15.  “Arvinas Announces Submission of New Drug Application to U.S. FDA for Vepdegestrant for Patients with ESR1-Mutated ER+/HER2- Advanced or Metastatic Breast Cancer” (Press release). Arvinas. 24 June 2025. Retrieved 17 September 2025.

External links

• Vepdegestrant information at Arvinas
• VERITAC-2 trial at ClinicalTrials.gov

Clinical data
Pronunciation	/ˌvɛpdəˈdʒɛstrənt/ VEP-də-JES-trənt
Other names	ARV-471
Legal status
Legal status	Investigational
Identifiers
IUPAC name
CAS Number	2229711-68-4
PubChem CID	134562533
ChemSpider	114935295
UNII	WC1U3R1YMI
ChEMBL	ChEMBL5095210
Chemical and physical data
Formula	C45H49N5O4
Molar mass	723.918 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

• Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and ChallengesPublication Name: Journal of Medicinal ChemistryPublication Date: 2023-06-28PMID: 37377342DOI: 10.1021/acs.jmedchem.3c00136
• Emerging targeted protein degradation tools for innovative drug discovery: From classical PROTACs to the novel and beyondPublication Name: European Journal of Medicinal ChemistryPublication Date: 2022-03-05PMID: 35092900DOI: 10.1016/j.ejmech.2022.114142
• Structural and Physicochemical Features of Oral PROTACsPublication Name: Journal of Medicinal ChemistryPublication Date: 2024-07-30PMID: 39078401DOI: 10.1021/acs.jmedchem.4c01017
• Discovery of the cereblon-recruiting tubulin PROTACs effective in overcoming Taxol resistance in vitro and in vivoPublication Name: European Journal of Medicinal ChemistryPublication Date: 2024-02-05PMID: 38171146DOI: 10.1016/j.ejmech.2023.116067
• Current advances and development strategies of orally bioavailable PROTACsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2023-12-05PMID: 37708797DOI: 10.1016/j.ejmech.2023.115793
• Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor ActivityPublication Name: Journal of Medicinal ChemistryPublication Date: 2023-08-30PMID: 37647546DOI: 10.1021/acs.jmedchem.3c01186
• Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader ProbesPublication Name: Journal of Medicinal ChemistryPublication Date: 2023-07-05PMCID: PMC10388296PMID: 37403870DOI: 10.1021/acs.jmedchem.3c00550

////////////vepdegestrant, anax lab, approvals 2026, fda 2026, Veppanu, FDA 2026, APROVALS 2026, Veppanu, ARV 471, WC1U3R1YMI, PF 07850327