Androgen Receptor (AR). BMS-986365 is a heterobifunctional ligand-directed degrader (LDD) that induces CRL4^CRBN E3 ligase-dependent ubiquitination and degradation of AR, and also acts as a competitive antagonist. [2]
Androgen receptor (AR wild-type and mutants, including those resistant to enzalutamide).

BMS-986365 is a heterobifunctional ligand-directed degrader (LDD) that enables CRL4CRBN E3 ligase-dependent ubiquitination and degradation of the androgen receptor (AR), with a DC50 of 10 to 40 nM and a Ymin of 7% to 19%. It is a highly potent and selective AR degrader that induces rapid and deep degradation of both wild-type and mutant forms of the receptor residing in either the cytoplasmic or nuclear compartments of the cell. The drug is approximately 100-fold more potent than enzalutamide (ENZ) at inhibiting androgen-stimulated transcription of AR target genes, and 10- to 120-fold more potent than ENZ at inhibiting AR-dependent proliferation of multiple prostate cancer cell lines in vitro. [1]

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AR Degradation Potency & Selectivity: In VCaP and LNCaP cells, BMS-986365 degrades AR with a DC₅₀ of 7 nM and 29 nM, and a Y_min of 7% and 17%, respectively. It rapidly and efficiently degrades wild-type and several clinically relevant AR mutants (e.g., T878A, H875Y, W742C, F877L), but does not degrade AR-V7. The half-life (t_1/2) of AR degradation in VCaP cells at 500 nM was approximately 0.6 hours. [2]
Antiproliferative Activity: In the presence of 0.1 nM R1881, BMS-986365 inhibited proliferation of VCaP and LNCaP cells with GI₅₀ values of 11 nM and 4 nM, respectively, showing ~50- to 100-fold greater potency than enzalutamide. In LNCaP cells overexpressing AR^WT or mutants (F877L, H875Y, W742C), GI₅₀ values ranged from 3 to 36 nM, exhibiting 10- to 120-fold greater potency than enzalutamide. The GI₅₀ for the AR L702H mutant was 0.24 μM, about 10-fold more potent than enzalutamide. It showed no significant antiproliferative effect in AR-negative PC3 or AR-V7-dependent 22Rv1 cells. [2]
Inhibition of AR Signaling: BMS-986365 inhibited R1881-stimulated AR target gene (FKBP5) expression in VCaP cells with an IC₅₀ of 1 nM, approximately two orders of magnitude more potent than enzalutamide. NanoString analysis of 114 AR-regulated genes showed that BMS-986365 reversed R1881-mediated AR-dependent transcription more rapidly (within 6 hours) and more completely than enzalutamide. [2]
Mechanism of Action: BMS-986365 induces CRBN- and proteasome-dependent AR degradation. Blocking degradation with the high-affinity CRBN binder CC-220 revealed that BMS-986365 also possesses substantial intrinsic antagonist activity, with potency comparable to enzalutamide, demonstrating its dual mechanism of action (degradation and antagonism). [2]
Proteomics Selectivity: Global proteomics analysis in LNCaP cells treated with 1 μM BMS-986365 for 6 hours showed that AR was the only protein downregulated more than 2-fold (to 15% of DMSO control). No significant degradation was observed for estrogen receptor (ER), progesterone receptor (PR), glucocorticoid receptor (GR), or known CRBN neosubstrates like ZFP91 and GSPT1. [2]

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In vitro, BMS-986365 potently and rapidly degrades both wild-type and mutant AR with DC50 values between 10-40 nM across multiple prostate cancer cell lines. Compared with enzalutamide, BMS-986365 more efficiently inhibits AR target gene transcription and AR-dependent proliferation of prostate cancer cell lines. Whereas enzalutamide increased AR protein in metastatic CRPC models, BMS-986365 maintained low levels of AR protein despite increased AR transcript levels, confirming its degradation-dependent mechanism (DC50 = 10-40 nM).

In animal models of advanced prostate cancer, BMS-986365 demonstrates on-target activity, degrading AR, suppressing AR signaling, and inhibiting tumor growth. In validated models of advanced castration-resistant prostate cancer (CRPC) and therapy-resistant patient-derived xenografts, including those with acquired resistance to ENZ, BMS-986365 achieved tumor volume reductions of 63–92%. Preclinical data collectively indicate that BMS-986365 is superior to standard-of-care AR antagonists, such as ENZ, in disease-relevant animal models. [1]

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AR Degradation & Pharmacodynamics: In NSG mice bearing VCaP tumors, oral administration of BMS-986365 (30 mg/kg, QD for 3 days) reduced intratumoral AR levels to 91% and 83% of control at 6 and 24 hours post-last dose, respectively. In dogs and cynomolgus monkeys, BMS-986365 dose-dependently degraded AR in epididymis tissue. [2] Antitumor Efficacy: VCaP Model: In nude mice bearing VCaP tumors, oral BMS-986365 (30 mg/kg) achieved 81% tumor volume reduction, compared to 51% with enzalutamide (30 mg/kg). In castrated mice, BMS-986365 achieved 76% tumor volume reduction. [2] Enzalutamide-Resistant VCaP Model: In the acquired resistant EnzR-VCaP model, BMS-986365 (3, 10, 30 mg/kg) dose-dependently inhibited tumor growth, achieving 92% tumor volume reduction at 30 mg/kg. [2] Patient-Derived Xenograft Models: In multiple prostate cancer PDX models, BMS-986365 (30 mg/kg) demonstrated potent antitumor activity. In the ARPI-resistant CTG-2440 model, BMS-986365 showed superior antitumor activity compared to enzalutamide and maintained lower AR protein levels. [2]

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In vivo, BMS-986365 demonstrates on-target activity degrading AR, suppressing AR signaling, and inhibiting tumor growth in animal models of advanced prostate cancer. It achieves tumor volume reductions of 63-92% in therapy-resistant patient-derived xenografts (PDXs), including those with acquired resistance to enzalutamide. It shows efficacy in both cell line- and PDX-derived xenograft models of castration-sensitive prostate cancer and advanced/therapy-resistant CRPC. Clinically, it reduced PSA in patients with metastatic CRPC after ARPI, including patients with wild-type AR.

AR Binding Affinity: The binding affinity of BMS-986365 to AR was determined using a radioactive ligand competition binding assay. Recombinant human AR protein (containing the ligand-binding domain) was incubated with radiolabeled testosterone and increasing concentrations of the test compound. The results showed that BMS-986365 binds AR with affinity similar to testosterone and approximately 10-fold higher than enzalutamide. [2]

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The binding affinity of BMS-986365 to AR was assessed via radioligand displacement assays using [3H]-DHT or [3H]-R1881 to determine Kd and IC50 values against both wild-type and mutant AR isoforms. CRBN binding was characterized using fluorescence polarization (FP) or surface plasmon resonance (SPR) assays with recombinant CRBN-DDB1 complex. Target engagement and degradation kinetics were evaluated using NanoBRET assays in live cells expressing AR-CRBN fusion constructs.

AR Degradation Quantification (ELISA): VCaP or LNCaP cells were seeded in 96-well plates. After attachment, cells were treated with BMS-986365 at a 10-point, 1:3 serial dilution starting from 5 μM using an HP D300 Digital Dispenser for 24 hours. Cells were then lysed, and AR protein levels in the lysates were quantified using a Total Androgen Receptor ELISA Kit to calculate DC₅₀ and Y_min. [2]
AR Degradation Kinetics (Western Blot): VCaP or LNCaP cells were seeded in 6-well plates in phenol red-free medium with 5% charcoal-stripped FBS. After 24-48 hours of starvation, cells were treated with BMS-986365 (concentrations ranging from 5-5000 nM) along with 0.1 nM R1881. Cells were harvested at various time points (0.25, 0.5, 1, 2, 4, 6, 16, 24 hours), lysed, and AR protein levels were analyzed by Western blot using antibodies against AR and tubulin. [2]
AR Synthesis and Turnover Rate (SILAC-MS): VCaP and LNCaP cells were cultured in SILAC media with heavy isotopes of lysine and arginine, along with 0.1 nM R1881, and treated with DMSO, 1 μM enzalutamide, or BMS-986365 (100 nM or 1 μM). Cells were harvested at 0.5, 1, 3, 6, 12, 24, 48 hours. The ratio of heavy (newly synthesized) to light (old) AR peptides was determined by LC-MS to calculate AR degradation half-life. [2]
AR Target Gene Expression Inhibition (bDNA): VCaP or LNCaP cells were seeded in 96-well plates in starvation medium. After 24 hours, cells were treated with BMS-986365 (0.0005 to 10 μM, 10-point 1:3 dilution) and 0.3 nM R1881 for 24 hours. A CC-220 competition group (30 μM) was included. Cells were lysed, and mRNA levels of the AR target gene FKBP5 and the housekeeping gene RPL13A were measured using the QuantiGene 2.0 Singleplex bDNA Assay to determine IC₅₀. [2]
Cell Proliferation Inhibition (CTG): VCaP or LNCaP cells were seeded in 384-well plates in starvation medium. After 24-72 hours, cells were treated with BMS-986365 (10-point 1:3 dilution starting from 10 μM) and/or 0.1 nM R1881 for 168 hours. Cell viability was assessed using the CellTiter-Glo (CTG) reagent by measuring ATP levels to calculate GI₅₀. [2]

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Prostate cancer cell lines (VCaP, LNCaP, 22Rv1, and enzalutamide-resistant derivatives) were treated with BMS-986365 at concentrations ranging from 0.1 nM to 1 uM for 4-72 hours. AR protein levels were quantified by Western blotting and In-Cell Western (ICW) assays to determine DC50. AR target gene expression (KLK3, TMPRSS2, NKX3.1) was assessed by qRT-PCR. Cell proliferation was measured by CellTiter-Glo assay over 5-7 days of treatment. Cell cycle analysis was performed by propidium iodide staining flow cytometry.

Pharmacodynamic Study: Male NSG mice bearing VCaP tumors (~500 mm³) were dosed orally with vehicle or BMS-986365 (30 mg/kg) once daily for 3 consecutive days (n=8). Plasma and tumor samples were collected at 2, 6, and 24 hours post-last dose. Compound concentrations were measured in plasma by LC/MS. AR protein levels in tumors were assessed by Western blot. [2]
Efficacy Study (VCaP): VCaP cells were implanted subcutaneously in the right flank of male J/nu mice. When tumors reached ~150 mm³, mice were randomized (n=4-7/group) and treated orally once daily with BMS-986365 (1, 3, 10, 30 mg/kg) or enzalutamide (30 mg/kg) for 21 days. Tumor volumes were measured three times weekly (calculated as length × width²/2) to determine tumor growth inhibition. [2]
Efficacy Study (Enzalutamide-Resistant VCaP Model): EnzR-VCaP cells were implanted subcutaneously in NSG mice. When tumors reached ~150 mm³, mice were randomized (n=10/group) and treated orally once daily with BMS-986365 (3, 10, 30 mg/kg) or vehicle for 45 days. Tumor volumes were measured regularly. [2]
Efficacy Study (PDX Models): Patient-derived xenograft (PDX) fragments or single-cell suspensions were implanted into NSG or J/nu mice. When tumors reached ~150-200 mm³, mice were randomized and treated orally once daily with BMS-986365 (30 mg/kg) or enzalutamide (30 or 50 mg/kg) for several weeks (duration varied by model). Tumor volumes were measured weekly, and tumors were harvested at endpoint for Western blot, IHC, or RNA-seq analysis. [2]

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Patient-derived xenograft (PDX) models of CRPC (including enzalutamide-resistant models) were established in immunocompromised mice. BMS-986365 was administered orally at doses ranging from 1-30 mg/kg once daily (QD) for 4-6 weeks. Tumor volume was measured bi-weekly by calipers to calculate tumor growth inhibition (TGI) percentage. Plasma AR protein levels were measured as a pharmacodynamic (PD) biomarker. AR target gene expression and signaling pathway inhibition were assessed in tumor tissue lysates post-treatment.

Pharmacokinetics in Mice: Following a single intravenous dose of BMS-986365 (2 mg/kg) in CD1 mice, plasma clearance was 20.7 mL/min/kg, volume of distribution was 3.1 L/kg, and half-life was 1.7 hours. Following oral administration, the mean peak plasma concentration (C_max) was 0.275 μM, time to reach C_max (T_max) was 4.5 hours, and oral bioavailability (%F) was 40%. The product of the fraction absorbed and the fraction escaping the gut (fa x fg) was estimated to be 0.6. [2]
Pharmacokinetics in Patients: Exposure of BMS-986365 increased with dose, but less than proportionally at higher doses. The mean terminal half-life after a single dose ranged from 20-28 hours. At steady-state (Day 29), the geometric mean area under the curve over 24 hours (AUC_0-24h) was 22.97, 25.88, and 40.17 μg·h/mL for the 400 mg, 600 mg, and 900 mg BID dose groups, respectively. [3]

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BMS-986365 is orally bioavailable with favorable pharmacokinetic properties. In rodent models, it achieves plasma concentrations sufficient for sustained AR degradation with once-daily oral dosing. The compound has a molecular weight of 818.92, XLogP of 2.77, and is formulated for oral administration. It shows high solubility in DMSO (100 mg/mL). Storage recommendations: powder at -20degC for 12 months, in-solvent at -80degC for 6 months. Clinical pharmacokinetics demonstrate effective drug exposure in patients with metastatic CRPC.

Clinical Safety: The most common treatment-related adverse events (TRAEs) were asymptomatic prolonged QTc interval (47% all grade) and bradycardia (34%). No grade 4 or 5 TRAEs were reported. Grade 3 TRAEs occurred in 12% of patients, primarily QTc prolongation (9%). All QTc prolongations were asymptomatic and resolved with dose modification. No treatment discontinuations due to QTc prolongation or any other TRAE occurred. [3]
Ocular Adverse Events: In Part B, 21% of patients experienced treatment-emergent adverse events (TEAEs) of eye disorders, with 10% reporting photopsia (all grade 1). [3]

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Toxicology data from non-clinical safety studies is not fully disclosed in public resources. As an investigational new drug, BMS-986365 has undergone extensive preclinical toxicology assessment in rodent and non-rodent species to support clinical trials. Standard adverse effects related to AR degradation may include fatigue, hot flashes, and gynecomastia. Hepatotoxicity and cardiovascular effects have been monitored in clinical trials. The compound is not approved for general human use and is only available for clinical trial participants and laboratory research.

[1]. Abstract ND02: Discovery of BMS-986365, a ligand-directed androgen receptor degrader (AR LDD) with a dual mechanism-of-action and best-in-class potential, for the treatment of advanced prostate cancerJ. Cancer Research, 2024, 84(7_Supplement): ND02-ND02.

[2]. Discovery of BMS-986365, a First-in-Class Dual Androgen Receptor Ligand-Directed Degrader and Antagonist, for the Treatment of Advanced Prostate Cancer. Clin Cancer Res. 2026 Jan 6;32(1):224-241.

[3]. Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2025 Jan;36(1):76-88.

Background & Mechanism of Action: The Androgen Receptor (AR) is a key driver in prostate cancer. BMS-986365 is a first-in-class dual AR ligand-directed degrader and antagonist, designed to overcome resistance to current AR pathway inhibitors via a dual mechanism: degradation of AR protein and competitive antagonism of AR signaling. It works by binding to the AR ligand-binding domain and the E3 ubiquitin ligase CRBN, inducing AR ubiquitination and proteasomal degradation. [2]
Preclinical Advantages: Preclinical data suggest that BMS-986365 achieves more potent and deeper inhibition of AR signaling compared to standard-of-care AR antagonists like enzalutamide, and demonstrates superior antitumor activity in multiple disease-relevant animal models, including those resistant to enzalutamide. Its design balances degradation potency with low intrinsic agonism, minimizing the risk of agonistic activity and ensuring residual AR activity is inhibited via antagonism even if degradation is incomplete. [2]
Clinical Efficacy: In a Phase I trial, BMS-986365 showed encouraging clinical activity in heavily pre-treated patients with mCRPC who progressed on prior ARPIs. In Part B at the 400-900 mg BID doses, the PSA50 response rate was 32% (50% in the 900 mg BID group). The median radiographic progression-free survival (rPFS) was 6.3 months (8.3 months in the 900 mg BID group). Efficacy was observed in patients with both AR ligand-binding domain wild-type and mutant tumors. [3]
Indication: Metastatic castration-resistant prostate cancer (mCRPC). [2, 3]

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BMS-986365 (Dezandrodeg) is a PROTAC-type AR degrader discovered by Bristol-Myers Squibb. It entered clinical trials (NCT05517304, NCT06072690) for the treatment of metastatic castration-resistant prostate cancer (CRPC) after progression on AR pathway inhibitors. It degrades AR via a CRBN-based PROTAC mechanism, offering advantages over traditional AR antagonists. The compound was designated an International Nonproprietary Name (INN) by the WHO INN proposed list 134 (February 2026). It is strictly for clinical trial and research use only and not commercially available as a therapeutic drug.

C41H45F3N8O5S

818.906818151474

818.318572

C, 60.13; H, 5.54; F, 6.96; N, 13.68; O, 9.77; S, 3.91

2446928-30-7

2446928-30-7; 2446929-86-6; 3107540-86-0 (besylate); 2446928-31-8 (HCl); 2446929-85-5 (RS-isomer); 2446928-32-9 (S-isomer);

149429863

Solid powder ; White to off-white

5.4

3

13

12

58

1590

1

S=C1N(C2C=CC(C#N)=C(C(F)(F)F)C=2)C(C(C)(C)N1C1C=CC(=C(CC)C=1)OCCN1CCN(CC(NC2C=CC=C(C=2)NC2C(NC(CC2)=O)=O)=O)[C@H](C)C1)=O

YUVGVJYLOFTILT-NHYGQJMQSA-N

InChI=1S/C41H45F3N8O5S/c1-5-26-19-31(52-39(58)51(38(56)40(52,3)4)30-10-9-27(22-45)32(21-30)41(42,43)44)11-13-34(26)57-18-17-49-15-16-50(25(2)23-49)24-36(54)47-29-8-6-7-28(20-29)46-33-12-14-35(53)48-37(33)55/h6-11,13,19-21,25,33,46H,5,12,14-18,23-24H2,1-4H3,(H,47,54)(H,48,53,55)/t25-,33?/m1/s1

2-[(2R)-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-ethylphenoxy]ethyl]-2-methylpiperazin-1-yl]-N-[3-[(2,6-dioxopiperidin-3-yl)amino]phenyl]acetamide

CC-94676; BMS-986365; 2446928-30-7; BMS986365; CC94676; 2-((R)-4-(2-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide; 2-[(2R)-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-ethylphenoxy]ethyl]-2-methylpiperazin-1-yl]-N-[3-[(2,6-dioxopiperidin-3-yl)amino]phenyl]acetamide;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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 (~122.11 mM; with ultrasonication)

Solubility in Formulation 1: ≥ 3.75 mg/mL (4.58 mM) (saturation unknown) in 10% DMSO 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 37.5 mg/mL clear DMSO stock solution and add it to 900 μL corn oil and mix well.

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