UT-34 (UT34) is a novel, selective, and orally bioavailable pan-androgen receptor (AR) antagonist and also a selective androgen receptor degrader (SARD) with anti-prostate cancer activity. It inhibits wild-type, F876L and W741L AR with IC50s of 211.7 nM, 262.4 nM and 215.7 nM, respectively. UT-34 binds to ligand-binding domain (LBD) and function-1 (AF-1) domains and requires ubiquitin proteasome pathway to degrade the AR.
Physicochemical Properties
| Molecular Formula | C15H12F4N4O2 |
| Molecular Weight | 356.274996757507 |
| Exact Mass | 356.089 |
| CAS # | 2168525-92-4 |
| PubChem CID | 132214622 |
| Appearance | White to off-white solid powder |
| LogP | 1.3 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 25 |
| Complexity | 549 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | FC1C=NN(C=1)C[C@](C(NC1C=CC(C#N)=C(C(F)(F)F)C=1)=O)(C)O |
| InChi Key | YDRMSDHDYRAUBR-AWEZNQCLSA-N |
| InChi Code | InChI=1S/C15H12F4N4O2/c1-14(25,8-23-7-10(16)6-21-23)13(24)22-11-3-2-9(5-20)12(4-11)15(17,18)19/h2-4,6-7,25H,8H2,1H3,(H,22,24)/t14-/m0/s1 |
| Chemical Name | (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluoropyrazol-1-yl)-2-hydroxy-2-methylpropanamide |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
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| ln Vitro | The expression of PSA and FKBP5, as well as the proliferation of LNCaP cells, are inhibited by UT-34 (3-10 μM; 24 hours); the largest effect is seen at 10 μM [1]. The effect starts at 100 nM. AR levels at 1000 nM in LNCaP cells decreased after treatment with UT-34 (0.1–10 μM; 24 hours) [1]. AR protein levels were downregulated when ZR-75-1 cells were maintained in serum growth media containing UT-34, but not the levels of progesterone receptors (PR) or estrogen receptors (ER). Moreover, UT-34 promoted downregulation of AR but not GR in MDA-MB-453 breast cancer cells that expressed both glucocorticoid receptor (GR) and AR [1]. AR and AR-V7 can be effectively degraded by UT-34. For a whole day, either 10 ng/mL doxycycline or 0.1 nM R1881, or both, were added to LNCaP-ARV7 cells. UT-34 inhibits the expression of EDN2, which is induced by doxycycline, and UT-34 also inhibits the expression of the FKBP5 gene, which is activated by R1881, [1]. | |
| ln Vivo | Seminal vesicle weight was decreased by 10%–20% and 50%–60%, respectively, by UT-34 at 20 and 40 mg/kg (20–40 mg/kg; oral; daily; 14 days; NSG mice) [1]. Rat prostate and seminal vesicles, as well as enzalutamide-resistant castration-resistant prostate cancer (CRPC) xenografts, are examples of androgen-dependent tissues whose proliferation is inhibited by UT-34. In rats with intact immunocompromised immune systems, UT-34 also causes tumor regression [1]. | |
| Cell Assay |
Cell Viability Assay[1] Cell Types: LNCaP cells Tested Concentrations: 3 µM, 10 µM Incubation Duration: 24 hrs (hours) Experimental Results: Inhibited the expression of PSA and FKBP5 and growth of LNCaP cells starting from 100 nM with maximum effect observed at 10 μM. Western Blot Analysis[1] Cell Types: LNCaP cells Tested Concentrations: 0.1 µM, 1 µM, 10 µM Incubation Duration: 24 hrs (hours) Experimental Results: Resulted in a reduction of AR levels at 1000 nM. |
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| Animal Protocol |
Animal/Disease Models: Non obese diabetic/severe combined immunodeficiency Gamma (NSG) mice injected with MR49F cells[1] Doses: 20 mg/kg or 40 mg/kg Route of Administration: Oral administration; daily; for 14 days Experimental Results: decreased the seminal vesicle weight . |
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| References |
[1]. Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer. Clin Cancer Res. 2019 Nov 15;25(22):6764-6780. [2]. Stone L. UT-34: a promising new AR degrader. Nat Rev Urol. 2019 Nov;16(11):640. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~250 mg/mL (~701.71 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 20.8 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (5.84 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8068 mL | 14.0339 mL | 28.0678 mL | |
| 5 mM | 0.5614 mL | 2.8068 mL | 5.6136 mL | |
| 10 mM | 0.2807 mL | 1.4034 mL | 2.8068 mL |