PROTAC-VHL-ligand or Protein degrader 1 is a novel and potent small molecule ligand for VHL (Von Hippel-Lindau), an E3 ligase which has been targeted by many PROTACs (proteolysis-targeting chimeras) degarders. Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method for inducing targeted protein degradation involves the use of PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired protein of interest. PROTACs have been successfully used to degrade numerous proteins in cells, but the peptidic E3 ligase ligands used in previous PROTACs have hindered their development into more mature chemical probes or therapeutics.

Physicochemical Properties

Molecular Formula	C22H30N4O3S
Molecular Weight	430.564
Exact Mass	430.203
Elemental Analysis	C, 61.37; H, 7.02; N, 13.01; O, 11.15; S, 7.45
CAS #	1448297-52-6
Related CAS #	1448297-52-6;1448189-80-7 (HCl);
PubChem CID	89702519
Appearance	White to light yellow solid powder
Density	1.3±0.1 g/cm3
Boiling Point	691.6±55.0 °C at 760 mmHg
Flash Point	372.1±31.5 °C
Vapour Pressure	0.0±2.3 mmHg at 25°C
Index of Refraction	1.604
LogP	0.85
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	6
Heavy Atom Count	30
Complexity	618
Defined Atom Stereocenter Count	3
SMILES	C1=NC(C)=C(C2C=CC(CNC(=O)[C@@H]3C[C@@H](O)CN3C(=O)C(N)C(C)(C)C)=CC=2)O1
InChi Key	ZLOXMSNKPDWMEF-ZIFCJYIRSA-N
InChi Code	InChI=1S/C22H30N4O3S/c1-13-18(30-12-25-13)15-7-5-14(6-8-15)10-24-20(28)17-9-16(27)11-26(17)21(29)19(23)22(2,3)4/h5-8,12,16-17,19,27H,9-11,23H2,1-4H3,(H,24,28)/t16-,17+,19-/m1/s1
Chemical Name	(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
Synonyms	VHL-7526 TFA; VHL-7526; PROTAC-VHL-ligand; Protein degrader 1 TFA; VH032-NH2 TFA; VHL ligand 1 TFA; Protein degrader 1 TFA , VHL7526; VHL 7526 trifluoroacetic acid
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

References

ACS Chem Biol.2015 Aug 21;10(8):1831-7.

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~232.26 mM) H2O : ≥ 25 mg/mL (~58.06 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.81 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 25.0 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: ≥ 2.5 mg/mL (5.81 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 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.81 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 25.0 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	2.3226 mL	11.6128 mL	23.2256 mL
	5 mM	0.4645 mL	2.3226 mL	4.6451 mL
	10 mM	0.2323 mL	1.1613 mL	2.3226 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.