Thalidomide-O-amido-C4-NH2 HCl is a ligand (for E3 ligase )-linker conjugate composed of Thalidomide (ligand for E3 ligase cereblon/CRBN) and a linker, may be utilized to prepare PROTAC protein degraders.

Physicochemical Properties

Molecular Formula	C19H23CLN4O6
Molecular Weight	438.8621
Exact Mass	438.13
CAS #	2245697-86-1
PubChem CID	134160248
Appearance	White to off-white solid powder
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	8
Heavy Atom Count	30
Complexity	696
Defined Atom Stereocenter Count	0
SMILES	Cl[H].O(C([H])([H])C(N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H])=O)C1=C([H])C([H])=C([H])C2=C1C(N(C2=O)C1([H])C(N([H])C(C([H])([H])C1([H])[H])=O)=O)=O
InChi Key	UZDTXDUTMCCMDO-UHFFFAOYSA-N
InChi Code	InChI=1S/C19H22N4O6.ClH/c20-8-1-2-9-21-15(25)10-29-13-5-3-4-11-16(13)19(28)23(18(11)27)12-6-7-14(24)22-17(12)26;/h3-5,12H,1-2,6-10,20H2,(H,21,25)(H,22,24,26);1H
Chemical Name	N-(4-aminobutyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetamide;hydrochloride
Synonyms	ThalidomideOamidoC4NH2 HCl; Thalidomide O amido C4 NH2 HCl
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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.
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

ln Vitro

One amine intermediate that can be employed as a heterobifunctional PROTAC BET degrader is thalidomide-O-amido-C4-NH2 (Compound 41). The proteins that make up the bromodomain and extra-terminal (BET) family, which includes testis-specific BRDT members, BRD2, BRD3, and BRD4, are known as epigenetic "readers" and are essential for controlling gene transcription. Therapeutic targets for cancer and other human disorders are thought to be appealing in the case of BET proteins. In order to cause BET protein degradation, heterobifunctional small-molecule BET degraders have recently been developed[1] using the proteolysis targeting chimera (PROTAC) idea. A degron-linker is thalidomide-O-amido-C4-NH2 (see Compound DL6-TL). Degron-linker-targeting ligand: in this system, the linker is covalently bound to a minimum of one degron and a minimum of one targeting ligand. The degron can bind to an E3 ubiquitin ligase, like cereblon, while the targeting ligand can bind to the targeted protein (s)[2].

References

[1]. Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins withPicomolar Cellular Potencies and Capable of Achieving Tumor Regression.J Med Chem. 2018 Jan 25;61(2):462-481. [2]. Methods to induce targeted protein degradation through bifunctional molecules. WO 2017024317 A2.

Solubility Data

Solubility (In Vitro)

DMSO : ~250 mg/mL (~569.66 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.74 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 (4.74 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 (4.74 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	2.2786 mL	11.3932 mL	22.7863 mL
	5 mM	0.4557 mL	2.2786 mL	4.5573 mL
	10 mM	0.2279 mL	1.1393 mL	2.2786 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.