We evaluate clinical progression of breakthrough candidates such as ARV-110 for prostate cancer, ARV-471 for breast cancer, and BTK degraders, while discussing critical challenges including the "hook effect" and oral bioavailability limitations. This review provides essential foundations for rational target selection, molecular optimization, and clinical translation strategies. By integrating mechanistic insights with clinical realities, this analysis offers perspectives on PROTAC technology advancement and identifies opportunities for transforming treatment of complex diseases resistant to conventional therapies.

2 months ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • STAT3 (Signal Transducer And Activator Of Transcription 3)

KRAS mutation • KRAS G12C • KRAS G12 • STAT3 mutation

bavdegalutamide (ARV-110) • vepdegestrant (ARV-471)

2ms

TACTIVE-E: ARV-471 in Combination With Everolimus for the Treatment of Advanced or Metastatic ER+, HER2- Breast Cancer (clinicaltrials.gov)

P1, N=32, Completed, Arvinas Estrogen Receptor, Inc. | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Aug 2025

2 months ago

Trial completion • Trial completion date

HER-2 (Human epidermal growth factor receptor 2)

everolimus • vepdegestrant (ARV-471)

3ms

TACTIVE-U Sub-Study A: TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study A) (clinicaltrials.gov)

P1/2, N=37, Active, not recruiting, Pfizer | Trial completion date: Sep 2025 --> Mar 2026 | Trial primary completion date: Sep 2025 --> Mar 2026

3 months ago

Trial completion date • Trial primary completion date

HER-2 (Human epidermal growth factor receptor 2)

HER-2 negative

Verzenio (abemaciclib) • vepdegestrant (ARV-471)

4ms

Effect of vepdegestrant, a PROTAC oestrogen receptor degrader, on dabigatran and rosuvastatin pharmacokinetics in healthy participants. (PubMed, Br J Clin Pharmacol)

Coadministration with vepdegestrant doubled dabigatran exposure and resulted in a minor increase (11%) in rosuvastatin exposure in humans.

4 months ago

PK/PD data • Journal

ER (Estrogen receptor)

vepdegestrant (ARV-471)

4ms

TACTIVE-U Sub-Study B: TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study B) (clinicaltrials.gov)

P1/2, N=20, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=47 --> 20

4 months ago

Enrollment closed • Enrollment change

HER-2 (Human epidermal growth factor receptor 2)

HER-2 negative

Kisqali (ribociclib) • vepdegestrant (ARV-471)

5ms

A Study to Learn How a Tablet Compared With an IV Infusion of the Study Medicine Called Vepdegestrant is Taken up Into the Blood in Healthy Adults (clinicaltrials.gov)

P1, N=10, Completed, Pfizer | Recruiting --> Completed

5 months ago

Trial completion

vepdegestrant (ARV-471)

5ms

Molecular Design of Novel Protein-Degrading Therapeutics Agents Currently in Clinical Trial. (PubMed, Pharmaceutics)

For instance, drugs like ARV-471 and ARV-110 are in advanced phases for treating metastatic breast cancer and prostate cancer, respectively, by targeting estrogen and androgen receptors. The conducted trials not only emphasize the therapeutic potential of protein degradation but also highlight the challenges associated with bioavailability, stability, and delivery mechanisms. As these clinical trials advance, they possess the potential to transform treatment paradigms, providing renewed hope for patients facing complex and refractory conditions.

5 months ago

Review • Journal

AR (Androgen receptor) • IKZF1 (IKAROS Family Zinc Finger 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)

bavdegalutamide (ARV-110) • vepdegestrant (ARV-471)

6ms

Targeting the Undruggable: Recent Progress in PROTAC-Induced Transcription Factor Degradation. (PubMed, Cancers (Basel))

Several clinically advanced PROTACs, including ARV-110 and ARV-471, demonstrate the therapeutic potential of this technology. Despite challenges in pharmacokinetics and E3 ligase selection, emerging data suggest that PROTACs can successfully target TFs, paving the way for new treatment strategies across oncology and other disease areas.

6 months ago

Review • Journal

ER (Estrogen receptor) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • AR (Androgen receptor) • CRBN (Cereblon) • BRD4 (Bromodomain Containing 4)

bavdegalutamide (ARV-110) • vepdegestrant (ARV-471)