TL13-12 is novel, potent and selective PROTAC degrader of anaplastic lymphoma kinase (ALK) with potential anticancer activity. It degrades ALK with DC50 values of 10 and 180 nM in H3122 and Karpas 299 cells, respectively. It comprises the cereblon E3 ligase ligand Pomalidomide conjugated to an ALK inhibitor. TL13-12 is the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. TL13-12 was developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. In some cell types, the degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).

Physicochemical Properties

Molecular Formula	C45H53CLN10O10S
Molecular Weight	961.481327772141
Exact Mass	960.335
CAS #	2229037-04-9
PubChem CID	138108740
Appearance	Yellow to brown solid powder
Density	1.4±0.1 g/cm3
Index of Refraction	1.639
LogP	1.06
Hydrogen Bond Donor Count	5
Hydrogen Bond Acceptor Count	17
Rotatable Bond Count	21
Heavy Atom Count	67
Complexity	1810
Defined Atom Stereocenter Count	0
InChi Key	WXNUIPVZMJMPNM-UHFFFAOYSA-N
InChi Code	InChI=1S/C45H53ClN10O10S/c1-28(2)67(62,63)37-10-5-4-8-33(37)50-41-31(46)26-49-45(53-41)51-32-12-11-29(25-36(32)64-3)55-18-16-54(17-19-55)20-22-66-24-23-65-21-15-47-39(58)27-48-34-9-6-7-30-40(34)44(61)56(43(30)60)35-13-14-38(57)52-42(35)59/h4-12,25-26,28,35,48H,13-24,27H2,1-3H3,(H,47,58)(H,52,57,59)(H2,49,50,51,53)
Chemical Name	N-[2-[2-[2-[4-[4-[[5-Chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]piperazin-1-yl]ethoxy]ethoxy]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]acetamide
Synonyms	TL-1312; TL13-12; TL1312; TL13 12;
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	DC50 for degrading ALK: 10 and 180 nM[1]
ln Vitro	ALK can be selectively degraded by TL13-12 (0-200 nM; 16 hours), with DC50s of 10 nM and 180 nM in H3122 cell and Karpas 299, respectively[1]. In Kelly and CHLA20 cells, TL13-12 (0-160 nM; 16 hours) decreases the expression of the ALK and aurora A proteins in a dose-dependent manner[1]. In CHLA20 cells, TL13-12 (100 nM; 16 hours) dramatically suppresses Tariqudan-induced ALK and Aurora A protein expression[1].
Cell Assay	Western Blot Analysis[1] Cell Types: Kelly and CHLA20 cells Tested Concentrations: 0 nM; 20 nM; 40 nM; 60 nM; 80 nM; 100 nM; 140 nM; 160 nM Incubation Duration: 16 hrs (hours) Experimental Results: demonstrated degrader behavior in cells. Western Blot Analysis[1] Cell Types: CHLA20 cells Tested Concentrations: 100 nM Incubation Duration: 16 hrs (hours) Experimental Results: diminished ALK and Aurora A protein expression.
References	[1]. Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK).J Med Chem. 2018 May 10;61(9):4249-4255.

Solubility Data

Solubility (In Vitro)

DMSO : ≥ 100 mg/mL (~104.01 mM)

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.0401 mL	5.2003 mL	10.4006 mL
	5 mM	0.2080 mL	1.0401 mL	2.0801 mL
	10 mM	0.1040 mL	0.5200 mL	1.0401 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.