bavdegalutamide (ARV-110) / Arvinas - LARVOL DELTA

Next-Generation Proteolysis-Targeting Chimeras in Precision Oncology: Multifunctional Designs, Emerging Modalities, and Translational Prospects in Targeted Protein Degradation. (PubMed, Drug Dev Res) - "Furthermore, ARV-110 and ARV-471, as two representative PROTACs, have entered clinical trials, suggesting their potentially broader application. Accordingly, this review provides a critical overview of the design rationales, molecular mechanisms of action, therapeutic utilities, and synthetic issues associated with these innovative modalities, focusing on on their translational implication and pharmacokinetic limitations, as well as potential future clinical applications."

Journal • Review • Oncology • Targeted Protein Degradation

Molecular Glue Degraders of AR/AR-V7: A Paradigm Shift in the Treatment of Advanced Prostate Cancer (PCF 2025) - "Clinically, AR-V7 is strongly associated with resistance to enzalutamide and abiraterone and is detected in >75% of advanced mCRPC cases, yet no inhibitors exist—underscoring a profound unmet need...In vivo, PK-optimized leads suppressed tumor growth in enzalutamide-resistant xenografts, outperformed ARV-110, the only AR-PROTAC degrader in clinical trials, by >10-fold, and showed excellent tolerability...Funding Acknowledgement: This work was supported by grants from the National Cancer Institute (NCI) Grant NIH T32 CA062948 (2020-2022) (C C Au), NIH-NCI Dual Fast Track phase I STTR/Phase II SBIR 1R42CA290913-01 (2024- 2027) (C C Au), First place of 2020 eBiomedical Business Plan Challenge (C C Au and P Giannakakou), The Daedalus Fund for Innovation award (P Giannakakou), The SPORE DRP award (P Giannakakou), DOD Grant W81XWH-19-1-0666 (P Giannakakou). I have the following relevant financial relationships to disclose: Co-founder of ARMA BIO, Corp"

Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • DDB1

Proteolysis-Targeting Chimera (PROTAC): Current Applications and Future Directions. (PubMed, MedComm (2020)) - "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."

Journal • Review • Breast Cancer • Genito-urinary Cancer • Hormone Receptor Breast Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • KRAS • STAT3

Covalent destabilizing degrader of AR and AR-V7 in androgen-independent prostate cancer cells (ACS-Fall 2025) - "Consistent with targeting both AR and AR-V7, we find that our molecule completely inhibits total AR transcriptional activity in androgen-independent prostate cancer cells expressing both AR and AR-V7 compared to AR antagonists or degraders that only target the ligand binding domain of full-length AR, such as enzalutamide and ARV-110. Taken together, our results highlight the utility of covalent ligand discovery approaches in directly targeting, destabilizing, inhibiting, and degrading classically undruggable transcription factor targets."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

In-cell proximity target validation methods for heterobifunctional molecules with CRBN- or VHL-binder using AirID. (PubMed, Commun Biol) - "Currently, cereblon (CRBN)- and von Hippel-Lindau (VHL)-binders with thalidomide- and VH032-backbones are widely used as E3 ligase binders. Analysis using ThBD-AirID revealed a nuclear interaction between androgen receptor and ARV-110. AirID-fused ThBD and VHL could be useful for validating the heterobifunctional molecular interactome in cells."

Journal • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • AR • CRBN

Trial of ARV-110 and Abiraterone in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC) (clinicaltrials.gov) - P1 | N=45 | Completed | Sponsor: Arvinas Androgen Receptor, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Apr 2025

Trial completion • Trial completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Synthesis of Two Versions of Carbon-14-Labeled ARV-110: An Androgen Receptor PROTAC Degrader for Prostate Cancer. (PubMed, J Labelled Comp Radiopharm) - "To support preclinical safety evaluations as well as studies of drug metabolism and pharmacokinetics, two versions of carbon-14-labeled ARV-110 were synthesized: N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-[1,3-14C2]dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (14C-ARV-110-a) and N-((1R,4R)-4-(3-chloro-4-[cyano-14C]cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (14C-ARV-110-b). The synthesis of 14C-ARV-110-a was initiated from 1,2-dibromo-4,5-difluorobenzene and zinc cyanide-14C (Zn(14CN)₂), while 14C-ARV-110-b was prepared from 2-chloro-4-fluoro[cyano-14C]benzonitrile."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR

Renal and Hepatic Effects of Androgen Receptor Downregulation by PROTAC ARV-110 in a Mouse Model of Polycystic Ovary Syndrome (ENDO 2025) - "DHT-VEH mice showed significant (p<0.05) increases in BW (1.14-fold), fat mass (2-fold), lean mass (1.09-fold), FG (1.29-fold), and impaired glucose tolerance (OGTT, AUC 1.47-fold) compared to CON-VEH. Both ARV-L and ARV-H treatments in DHT mice reduced BW, fat mass, FG, and OGTT without affecting lean mass. DHT-VEH-treated mice had increased kidney weight, UACR, and NGAL levels which were attenuated by ARV-110 in a dose-dependent manner."

Preclinical • Endocrine Disorders • Genetic Disorders • Genito-urinary Cancer • Hepatology • Liver Failure • Metabolic Disorders • Nephrology • Obesity • Oncology • Polycystic Ovary Syndrome • Prostate Cancer • Renal Disease • Solid Tumor • Targeted Protein Degradation • AR • KIM1

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."

Journal • Review • Breast Cancer • CNS Disorders • Genito-urinary Cancer • Hematological Malignancies • Immunology • Multiple Myeloma • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • IKZF1 • IRAK4

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."

Journal • Review • Oncology • Targeted Protein Degradation • AR • BRD4 • CRBN • ER • MYC

Covalent Destabilizing Degrader of AR and AR-V7 in Androgen-Independent Prostate Cancer Cells. (PubMed, J Am Chem Soc) - "Consistent with targeting both AR and AR-V7, we find that EN1441 completely inhibits total AR transcriptional activity in androgen-independent prostate cancer cells expressing both AR and AR-V7 compared with AR antagonists or degraders that only target the ligand-binding domain of full-length AR, such as enzalutamide and ARV-110. Our results put forth a pathfinder molecule EN1441 that targets an intrinsically disordered cysteine within AR to destabilize, degrade, and inhibit both AR and AR-V7 in androgen-independent prostate cancer cells and highlights the utility of covalent ligand discovery approaches in directly targeting, destabilizing, inhibiting, and degrading classically undruggable transcription factor targets."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Androgen Receptor PROTAC ARV-110 Ameliorates Metabolic Complications in a Mouse Model of Polycystic Ovary Syndrome. (PubMed, Endocrinology) - "Unbiased proteomics analysis revealed that ARV-110-H treatment severely affected the liver proteome and dysregulated multiple signaling and metabolic canonical pathways, while only minimal effects were observed with ARV-110-L treatment. In summary, our findings underscore the potential of AR PROTACs as a novel therapeutic approach for managing metabolic complications in PCOS, provided the dosing is carefully optimized to avoid adverse effects."

Journal • Preclinical • Endocrine Disorders • Hepatology • Polycystic Ovary Syndrome • Targeted Protein Degradation • AR • KIM1 • LEP

Applications of contemporary tools to measure plasma protein binding of targeted protein degraders. (PubMed, Drug Metab Dispos) - "Four exemplary PROTACs, cereblon-based ARV-110 and dTAG-13, and VHL-based ARV-771 and ERRα-degrader-3, were used to illustrate the challenges of obtaining accurate protein-binding results...Given the higher protein-binding assay failure rates with challenging compounds such as PROTACs, this study outlines strategies to improve assay efficiency. The results show improved efficiency in measuring plasma protein binding with PROTACs and provide insights for enhancing widely accepted protein-binding methods currently employed in drug research."

Journal • Targeted Protein Degradation • CRBN

Developing first-in-class AR-V7/AR-fl molecular glue degrader to revolutionize prostate cancer therapeutics (AACR 2025) - "Mechanistically, our lead compounds promoted Cullin-RING E3 ligase-mediated proteasomal degradation of AR-V7 and AR-fl within 4 hours, which was blocked by the proteasome inhibitor, bortezomib...Importantly, our lead compounds effectively reversed SoC treatment-resistance in preclinical models and demonstrated higher potency than enzalutamide or ARV-110 (AR-fl-PROTAC)...Collectively, these data support a first-in-class molecular glue degrader mechanism, enabling rapid degradation of both AR-fl and AR-V7 through targeting the AR NTD. In summary, our compounds offer a dual-targeting approach in a single treatment and have the potential to dramatically improve survival for patients with mCRPC and prevent the emergence of AR-V7 expression in patients with earlier-stage disease."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

CD36-mediated endocytosis of proteolysis-targeting chimeras. (PubMed, Cell) - "Here, using biotinylated chemical-probe-based target fishing and genetic knockdown/knockin approaches, we discovered that the membrane cluster of differentiation 36 (CD36) binds to and facilitates the uptake and efficacy of diverse PROTACs (e.g., SIM1-Me, MZ1, and clinical ARV-110) and large and/or polar small-molecule drugs (e.g., rapalink-1, rapamycin, navitoclax, birinapant, tubacin, and doxorubicin) via the CD36-mediated early endosome antigen 1 (EEA1)/Ras-related protein 5A (Rab5) endosomal cascade in vitro and/or in vivo. We then devised a novel chemical endocytic medicinal chemistry strategy to improve binding of PROTACs to CD36 using structural modifications via the prodrug approach, markedly enhancing PROTAC anti-tumor efficacy through spontaneously augmenting permeability and solubility."

Journal • Oncology • Targeted Protein Degradation • CD36 • RAB5A • SCARB1

A comprehensive mechanistic investigation of factors affecting intestinal absorption and bioavailability of two PROTACs in rats. (PubMed, Eur J Pharm Biopharm) - "In the rat, ARV-110 and ARV-471 were enzymatically degraded in the intestinal lumen and in plasma, and their intestinal permeability and systemic exposure seem to be reduced due to P-gp efflux."

Journal • Preclinical • Gastrointestinal Disorder • Targeted Protein Degradation

ARDENT: Trial of ARV-110 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=248 | Completed | Sponsor: Arvinas Inc. | Active, not recruiting ➔ Completed | Trial primary completion date: Jan 2025 ➔ Apr 2024

Trial completion • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Conquering PROTAC molecular design and drugability. (PubMed, Bioanalysis) - "Clinical successes, including ARV-110 for castration-resistant prostate cancer and ARV-471 for breast cancer, exemplify their ability to overcome resistance and provide durable effects. By addressing challenges in pharmacokinetics, safety, and scalability, PROTACs are poised to revolutionize precision medicine. This article presents a forward-looking perspective on conquering the molecular design and drugability of PROTACs, paving the path for transformative therapies."

Journal • Breast Cancer • Castration-Resistant Prostate Cancer • CNS Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation

Microwave-assisted synthesis of pomalidomide building blocks for rapid PROTAC and molecular glue development. (PubMed, Chem Commun (Camb)) - "Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method's utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs."

Journal • Targeted Protein Degradation

Covalent Destabilizing Degrader of AR and AR-V7 in Androgen-Independent Prostate Cancer Cells. (PubMed, bioRxiv) - "Consistent with targeting both AR and AR-V7, we find that EN1441 completely inhibits total AR transcriptional activity in androgen-independent prostate cancer cells expressing both AR and AR-V7 compared to AR antagonists or degraders that only target the ligand binding domain of full-length AR, such as enzalutamide and ARV-110. Our results put forth a pathfinder molecule EN1441 that targets an intrinsically disordered cysteine within AR to destabilize, degrade, and inhibit both AR and AR-V7 in androgen-independent prostate cancer cells and highlights the utility of covalent ligand discovery approaches in directly targeting, destabilizing, inhibiting, and degrading classically undruggable transcription factor targets."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Rapid and high-throughput screening of proteolysis targeting chimeras using a dual-reporter system expressing fluorescence protein and luciferase. (PubMed, BMC Biol) - "The dual-reporter system using both fluorescence and chemiluminescence was successfully constructed. Using this method, we identified effective candidate PROTACs against SIRT2. The dual-reporter system may accelerate drug discovery during PROTAC development."

Journal • Targeted Protein Degradation • SIRT2

Circulating tumor cell RNA biomarker for bavdegalutamide (ARV-110) in metastatic castration-resistant prostate cancer without AR T878/H875 mutations. (ASCO-GU 2025) - "Pre-treatment CTCm score 6 months in this small study mCRPC patients without AR T878/H875 mutations. Further investigation of the CTCm biomarker is warranted in mCRPC patients treated with bavdegalutamide and potentially other AR PROTACs."

Biomarker • Circulating tumor cells • Metastases • Tumor cell • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AGR2 • FAT1 • FOLH1 • HOXB13 • KLK2 • KLK3 • STEAP2

ARDENT: Trial of ARV-110 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=250 | Active, not recruiting | Sponsor: Arvinas Inc. | Trial primary completion date: Apr 2024 ➔ Jan 2025

Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Unleashing the Power of Covalent Drugs for Protein Degradation. (PubMed, Med Res Rev) - "Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field."

Journal • Review • Oncology • Solid Tumor • Targeted Protein Degradation • BTK • DDB1 • EGFR • KEAP1 • KRAS

Preclinical Evaluation of Bavdegalutamide (ARV-110), a Novel PROteolysis TArgeting Chimera Androgen Receptor Degrader. (PubMed, Mol Cancer Ther) - P1/2 | "Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone and enzalutamide) are standard treatments for metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer (mCRPC). These promising preclinical data supported clinical development of bavdegalutamide as a potential treatment for patients with prostate cancer. Bavdegalutamide was the first PROTAC protein degrader to enter human clinical trials, specifically in patients with mCRPC in a phase 1/2 study (NCT03888612)."

Journal • Preclinical • Castration-Resistant Prostate Cancer • Castration-Sensitive Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • CRBN