AR/androgen receptor

ARV-766 is a proteolysis targeting chimera (PROTAC®) that induces a protein-protein interaction between the AR and specific E3 ubiquitin ligase complexes, leading to the ubiquitination of AR and its subsequent degradation via the proteasome. In vitro, ARV-766 degrades AR in various prostate cancer cell lines, including those harboring resistance-conferring, clinically relevant point mutations, with a half-maximal degradation concentration (DC50) of <1 nM in wild type VCaP. Importantly ARV-766 also maintains potency against the AR L702H mutant, which has been associated with resistance to some AR antagonists[2].

In vivo, ARV-766 is orally bioavailable and robustly degrades AR with a >90% observed maximum degradation (Dmax) at efficacious doses. ARV-766 significantly and dose-dependently inhibits tumor growth in murine LNCaP and VCaP xenograft models, including an enzalutamide-insensitive non-castrated VCaP model. These preclinical data supported the clinical development of ARV-766 for the treatment of men with metastatic CRPC. Selected pre-clinical data along with the chemical structure of ARV-766 will be presented[2].

ARV-766 is an orally bioavailable PROTAC® protein degrader that targets the androgen receptor (AR) and is currently being developed for the treatment of prostate cancer in a phase 2 clinical trial. In vitro studies were conducted to assess the potential of ARV-766 to cause cytochrome P450 (CYP) and transporter-mediated drug-drug interactions (DDI). The induction potential of ARV-766 on CYP enzymes was assessed in cryopreserved human hepatocytes from three donors. Following treatment for 48 hours, mRNA levels for CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4 were determined by semiquantitative real-time polymerase chain reaction (PCR). The potential for ARV-766 to cause direct and time-dependent inhibition of the activities of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A was evaluated in pooled human liver microsomes (HLM). In addition, the inhibition potential against efflux transporters (Pgp and BCRP) and uptake transporters (MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2) was assessed using single transporter over-expressed cell monolayers (MDCK II or HEK293) or inside-out vesicles. DDI potential of ARV-766 as a victim via CYP mediated pathways was examined in HLM, human hepatocyte suspensions and recombinant CYP enzymes. ARV-766 as a substrate of Pgp and BCRP as well as OATP1B1 and 1B3 were assessed in Caco-2 and single transporter over-expressed HEK293 cells, respectively. The results showed that ARV-766 at concentrations ranging from 0.03 - 30 μM did not induce mRNA of CYP1A2, 2B6 and 2C9. Induction of CYP3A4 and CYP2C8 mRNA was observed with a maximal 2.5-8.8-fold (4-6% of positive control response) for CYP3A4 across all three hepatocyte lots, and a maximal 3.1-fold (28% of positive control response) for CYP2C8 in one of three lots. No direct or time-dependent inhibition was observed for any of the CYP isoforms after incubating HLM with ARV-766 at concentrations of 0.2-15 μM. ARV-766 did not inhibit any of the uptake transporters up to 3.75 μM tested except for MATE1 with IC50 value of 3.05 μM. ARV-766 inhibited BCRP with IC50 values of 0.21 μM (vesicle assay) and 1.55 μM (monolayer assay), and Pgp with IC50 values of 0.23 μM (vesicle assay) and >5 μM (monolayer assay). ARV-766 was relatively stable in HLM (up to 60 min), human hepatocyte suspension (up to 240 min) and major recombinant CYPs (up to 25 min) except for a 23% loss of parent with recombinant CYP3A5. Metabolite profiling using human plasma, HLM and human hepatocytes indicated that hydrolysis was the major metabolic pathway. Other minor pathways included oxidation, de-alkylation, and demethylation, which combined represent <2% of total abundance. ARV-766 exhibited low permeability in Caco-2 cell monolayers and the involvement of ARV-766 in an active efflux process was not reliably determined. In addition, ARV-766 was not likely a substrate for OATP1B1/3. These data demonstrate that ARV-766 has a low potential to cause significant DDI as an inhibitor or substrate of CYP enzymes. Clinical DDI studies with CYP3A inhibitors and inducers, and Pgp and BCRP substrates are being investigated. The 4β-hydroxy-cholesterol, a biomarker of CYP3A, is also being measured in the ongoing phase 2 clinical trial[1].

Patients with mCRPC inevitably develop resistance to available therapies and lack curative options. In patients treated with novel hormonal agents (NHAs), mutations can develop in the ligand-binding domain (LBD) of the AR gene, some of which are associated with resistance to current therapies and disease progression. ARV-766 is a novel, potent, orally bioavailable proteolysis targeting chimera (PROTAC) protein degrader that degrades not only wild-type AR but also clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. Here we describe a phase 2 expansion study to evaluate the clinical activity and safety of ARV-766 in men with mCRPC who have experienced disease progression on prior NHA therapy. Methods: This phase 2 cohort expansion is part of an open-label, first-in-human, phase 1/2 clinical trial of ARV-766 in men (aged ≥18 years) with histologically, pathologically, or cytologically confirmed mCRPC and Eastern Cooperative Oncology Group performance status score of 0 or 1. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor or orchiectomy is required. Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Following completion of dose escalation in the phase 1 portion of the study, which is evaluating the safety and tolerability of ARV-766, 2 doses (100 mg and 300 mg administered orally once daily in 28-day cycles) were selected for the phase 2 cohort expansion. The primary objectives of the cohort expansion study are to evaluate the antitumor activity of ARV-766 based on the overall response rate (per Response Evaluation Criteria in Solid Tumors) and the rates of prostate-specific antigen (PSA) declines of 30% (PSA30) and 50% (PSA50). Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140.[3]

Absorption and Administration: Luxdegalutamide is administered orally, once daily (QD), with food . The starting dose in clinical trials is 300 mg, with a lower dose of 100 mg available for evaluation if the starting dose is not tolerated .
Sampling and Analysis: Pharmacokinetic (PK) parameters are being assessed in an ongoing Phase I study (CJSB462A11101). Venous whole blood samples are collected to characterize plasma concentrations . Sampling time points include pre-dose (0 hour) and at 1, 2, 3, 4, 6, and 8 hours post-dose on Cycle 1 Day 1 and Day 21, with additional trough (0 hour) samples on Days 2 and 22 .
Key PK Parameters: The primary PK endpoints being evaluated are:
AUC (Area Under the Curve): Both AUClast (from time zero to the last quantifiable concentration) and AUCinf (extrapolated to infinite time) are being calculated .
Cmax: The maximum observed plasma concentration .
Tmax: The time to reach maximum plasma concentration .
Metabolite: The study is also evaluating the plasma concentrations of the major metabolite, ARV-767 .

Primary Objective: The primary goal of the ongoing Phase I study is to evaluate the safety and tolerability of Luxdegalutamide in patients with metastatic prostate cancer .
Dose-Limiting Toxicity (DLT): The incidence and severity of DLTs occurring during the first 28-day cycle are a key safety endpoint. A DLT is defined as a treatment-related adverse event that meets specific severity criteria outlined in the protocol .
Adverse Events (AEs): The study monitors the incidence, type, frequency, and severity of all Adverse Events (AEs) and Serious Adverse Events (SAEs) as graded by the NCI CTCAE version 5.0 .
Safety Monitoring: Safety assessments include:
Dose Adjustments: The number of participants requiring dose reductions, interruptions, or permanent discontinuation is being tracked .
Dose Intensity: The actual dose received relative to the planned dose is being calculated .
Study Termination: Treatment may be discontinued due to unacceptable toxicity, disease progression, death, or withdrawal of consent .

[1]. In vitro evaluation of PROTAC® degrader ARV-766 for cytochrome P450-and transporter-mediated drug-drug interaction. Drug Metabolism and Pharmacokinetics, 2024, 55: 100881.
[2]. Abstract ND03: Discovery of ARV-766, an androgen receptor degrading PROTAC® for the treatment of men with metastatic castration resistant prostate cancer. Cancer Research, 2023, 83(7_Supplement): ND03-ND03.
[3]. A phase 2 expansion study of ARV-766, a PROTAC androgen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC). 2023.https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.6_suppl.TPS290

Luxdegalutamide is an orally bioavailable androgen receptor (AR)-targeting protein degrader composed of an AR ligand linked to an E3 ubiquitin ligase recognition group and utilizing a proteolytic-targeting chimeric (PROTAC) technology, exhibiting potential antitumor activity. After oral administration, Luxdegalutamide targets and binds to the AR ligand-binding domain on AR. Subsequently, the E3 ubiquitin ligase recognition group of Luxdegalutamide recruits E3 ubiquitin ligase to AR, resulting in ubiquitin labeling of AR. This leads to ubiquitination and proteasome degradation of AR, thereby inhibiting the expression of AR target genes and blocking AR-mediated signaling. This inhibits the proliferation of AR-overexpressing tumor cells. Furthermore, the degradation of AR releases Luxdegalutamide, enabling it to bind to more AR cells. AR plays a crucial role in the proliferation of castration-resistant prostate cancer cells (CRPC). Luxdegalutamide can degrade resistance-driven point mutations in AR, including the L702H mutation associated with treatments such as abiraterone.

C45H54FN7O6

807.951974391937

807.41196

C, 66.90; H, 6.74; F, 2.35; N, 12.14; O, 11.88

2750830-09-0

156504141

White to off-white solid powder

5.9

3

11

11

59

1550

1

C(N[C@H]1CCC(=O)NC1=O)(=O)C1=CC=C(N2CCN(CC3CCN(C4=CC=C(C(N[C@@H]5C(C)(C)[C@@H](OC6=CC=C(C#N)C(OC)=C6)C5(C)C)=O)C=C4)CC3)CC2)C=C1F

RDPPBRKNBBXPNZ-PJXMSJPKSA-N

InChI=1S/C45H54FN7O6/c1-44(2)42(45(3,4)43(44)59-33-12-8-30(26-47)37(25-33)58-5)50-39(55)29-6-9-31(10-7-29)52-18-16-28(17-19-52)27-51-20-22-53(23-21-51)32-11-13-34(35(46)24-32)40(56)48-36-14-15-38(54)49-41(36)57/h6-13,24-25,28,36,42-43H,14-23,27H2,1-5H3,(H,48,56)(H,50,55)(H,49,54,57)/t36-,42?,43?/m0/s1

4-[4-[[1-[4-[[3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-N-[(3S)-2,6-dioxopiperidin-3-yl]-2-fluorobenzamide

Luxdegalutamide; ARV-766; 2750830-09-0; ARV766; 4-(4-((1-(4-((trans-3-(4-Cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)-2-fluorobenzamide; luxdegalutamide [INN]; 5BD7R933PV; CHEMBL5314528;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~123.77 mM)

Solubility in Formulation 1: 2.5 mg/mL (3.09 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)