SIAIS164018 is a PROTAC-based ALK and EGFR degrader with IC50s of 2.5 nM and 6.6 nM for ALK and ALK G1202R, respectively. SIAIS164018 strongly inhibits cancer/tumor cell migration and invasion, causes cell arrest in the G1 phase, and causes apoptosis. SIAIS164018 has better properties than Brigatinib.

Physicochemical Properties

Molecular Formula	C43H48CLN10O7P
Molecular Weight	883.330788612366
Exact Mass	882.313
CAS #	2353492-68-7
Related CAS #	SIAIS164018 hydrochloride
PubChem CID	141762856
Appearance	Typically exists as solid at room temperature
LogP	4.6
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	14
Rotatable Bond Count	12
Heavy Atom Count	62
Complexity	1690
Defined Atom Stereocenter Count	0
InChi Key	AQGLXXCBEXDRNS-UHFFFAOYSA-N
InChi Code	InChI=1S/C43H48ClN10O7P/c1-61-34-23-27(11-12-30(34)48-43-46-24-29(44)39(50-43)47-31-8-4-5-10-35(31)62(2,3)60)51-17-15-26(16-18-51)52-19-21-53(22-20-52)37(56)25-45-32-9-6-7-28-38(32)42(59)54(41(28)58)33-13-14-36(55)49-40(33)57/h4-12,23-24,26,33,45H,13-22,25H2,1-3H3,(H,49,55,57)(H2,46,47,48,50)
Chemical Name	4-[[2-[4-[1-[4-[[5-chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]piperidin-4-yl]piperazin-1-yl]-2-oxoethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
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 cells is considerably inhibited by SIAIS164018 (0–1 μM; 16 hours) [1]. Brigatinib was not as effective in inhibiting cell growth in ALK (G1202R)-overexpressing 293T and EGFR-expressing H1975 cell lines as SIAIS164018 (0-100 nM; 72 h) [1]. Significant G1 cell cycle arrest is induced in ALK-negative Calu-1 and MDA-MB-231 cells by SIAIS164018 (100 nM; 24 or 48 hours) [1]. In ALK-positive SR and ALK-negative Calu-1 cell lines, SIAIS164018 (0.01-1000 nM; 16h) down-regulates the protein levels of FAK, PYK2, FER, RSK1, and GAK [1].
Cell Assay	Cell proliferation experiment [1] Cell Types: SR cell Tested Concentrations: 0-1 μM Incubation Duration: 16 h Experimental Results: Dramatically inhibited SR cell proliferation, with an IC50 value of 2 nM. Cell proliferation assay[1] Cell Types: 293T overexpressing ALK (G1202R) and H1975 cell line expressing EGFR Tested Concentrations: 0-100 nM Incubation Duration: 72 hrs (hours) Experimental Results: Brigatinib demonstrated better performance compared to ALK (G1202R) Inhibitory effects on cell proliferation - 293T-expressing and EGFR-expressing H1975 cell lines, with IC50s of 21 and 42 nM, respectively. Cell cycle analysis[1] Cell Types: ALK negative Calu-1 and MDA-MB-231 cells Tested Concentrations: 100 nM Incubation Duration: 24 or 48 hrs (hours) Experimental Results: Significant induction in ALK negative Calu-1 and MDA-MB-231 cells The G1 cell cycle arrest of MDA-MB-231 cells. Western Blot Analysis[1] Cell Types: SR and Calu-1 Cell Tested Concentrations: 0.01, 0.1, 1, 10, 100 and 1000 nM Incubation Duration: 16 hrs (hours) Experimental Results: Down-regulated the protein level of FAK, PYK2, FER, RSK1, and GAK.
References	[1]. Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile. J Med Chem. 2021 Jul 8;64(13):9152-9165.

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~113.21 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.83 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.1321 mL	5.6604 mL	11.3208 mL
	5 mM	0.2264 mL	1.1321 mL	2.2642 mL
	10 mM	0.1132 mL	0.5660 mL	1.1321 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.