SIAIS117 is a potent Brigatinib-PROTAC protein degrader. SIAIS117 is an ALK PROTAC based on the combination of Brigatinib and VHL-1. SIAIS117 can effectively degrade ALK G1202R point mutation SIAIS117 can block the growth of SR and H2228 cancer/tumor cell lines. SIAIS117 has potential antiproliferation potential in small cell lung cancer.

Physicochemical Properties

Molecular Formula	C57H76CLN10O7PS
Molecular Weight	1111.77
Exact Mass	1110.504
CAS #	2353494-84-3
PubChem CID	141763005
Appearance	Typically exists as solid at room temperature
LogP	9.5
Hydrogen Bond Donor Count	6
Hydrogen Bond Acceptor Count	14
Rotatable Bond Count	25
Heavy Atom Count	77
Complexity	1920
Defined Atom Stereocenter Count	3
SMILES	CC1=C(SC=N1)C2=CC=C(C=C2)CNC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCC(=O)NC4CCN(CC4)C5=CC(=C(C=C5)NC6=NC=C(C(=N6)NC7=CC=CC=C7P(=O)(C)C)Cl)OC)O
InChi Key	DYUJLNPTOOBZBB-CCXZOALNSA-N
InChi Code	InChI=1S/C57H76ClN10O7PS/c1-37-51(77-36-61-37)39-23-21-38(22-24-39)33-59-54(72)46-32-42(69)35-68(46)55(73)52(57(2,3)4)65-50(71)20-14-12-10-8-9-11-13-19-49(70)62-40-27-29-67(30-28-40)41-25-26-44(47(31-41)75-5)64-56-60-34-43(58)53(66-56)63-45-17-15-16-18-48(45)76(6,7)74/h15-18,21-26,31,34,36,40,42,46,52,69H,8-14,19-20,27-30,32-33,35H2,1-7H3,(H,59,72)(H,62,70)(H,65,71)(H2,60,63,64,66)/t42-,46+,52-/m1/s1
Chemical Name	N-[1-[4-[[5-chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]piperidin-4-yl]-N'-[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]undecanediamide
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

ln Vitro	The proliferation of SR, H2228, NCI-H69, and NCI-H1688 cells is inhibited by SIAIS117 (0-10 μM, 72 h) with IC50 values of 1.7, 46, 799, and 259 nM, respectively [1]. SIAIS117 (0-500 nM, 24 hours) prevents ALK and STAT3 phosphorylation [1]. SIAIS117 breaks down G1202R-ALK protein and prevents the growth of G1202R mutant ALK cell lines [1]. In SR cells, SIAIS117 (100 nM, 24 hours) results in the long-term destruction of ALK protein [1].
Cell Assay	Cell proliferation experiment Cell Types: NSCLC cell line H2228, small cell lung cancer cell line (NCI-H69, NCI-H1688) [1] Tested Concentrations: 0-10 μM Incubation Duration: 72 h Experimental Results: Cell growth was inhibited approximately twice as much as The IC50 value is lower (46 nM) compared to SIAIS117NC (114 nM). It shows good growth inhibitory effects on NCI-H69 and NCI-H1688 cell lines, with IC50 values of 799 and 259 nM respectively. Western Blot Analysis Cell Types: SR, H2228[1] Tested Concentrations: 0, 1, 10, 50, 100, 500 nM Incubation Duration: 24 hrs (hours) Experimental Results: Inhibited all phosphorylation of ALK at 10 nM and inhibited pSTAT3, in H2228 cells, degraded ALK protein starting from 50 nM and Dramatically downregulated UCK2 and GAK. Resulting in continued degradation of ALK protein in SR cells.
References	[1]. Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance. Eur J Med Chem. 2020;193:112190.

Solubility Data

Solubility (In Vitro)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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	0.8995 mL	4.4973 mL	8.9947 mL
	5 mM	0.1799 mL	0.8995 mL	1.7989 mL
	10 mM	0.0899 mL	0.4497 mL	0.8995 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.