SIAIS178 is a potent and specific BCR-ABL degrader of the PROTAC class with IC50 of 24 nM. SIAIS178 degrades BCR-ABL proteins by recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. SIAIS178 has anti-tumor effects.

Physicochemical Properties

Molecular Formula	C50H62CLN11O6S2
Molecular Weight	1012.68038702011
Exact Mass	1011.401
CAS #	2376047-73-1
PubChem CID	139474625
Appearance	White to off-white solid powder
LogP	7.5
Hydrogen Bond Donor Count	5
Hydrogen Bond Acceptor Count	14
Rotatable Bond Count	19
Heavy Atom Count	70
Complexity	1750
Defined Atom Stereocenter Count	3
SMILES	ClC1=CC=CC(C)=C1NC(C1=CN=C(NC2=CC(=NC(C)=N2)N2CCN(C(CCCCCCC(N[C@H](C(N3C[C@@H](C[C@H]3C(NCC3C=CC(C4=C(C)N=CS4)=CC=3)=O)O)=O)C(C)(C)C)=O)=O)CC2)S1)=O
InChi Key	YGQREOJIRFCRKQ-ZIBKGDFVSA-N
InChi Code	InChI=1S/C50H62ClN11O6S2/c1-30-12-11-13-36(51)43(30)59-47(67)38-27-53-49(70-38)57-39-25-40(56-32(3)55-39)60-20-22-61(23-21-60)42(65)15-10-8-7-9-14-41(64)58-45(50(4,5)6)48(68)62-28-35(63)24-37(62)46(66)52-26-33-16-18-34(19-17-33)44-31(2)54-29-69-44/h11-13,16-19,25,27,29,35,37,45,63H,7-10,14-15,20-24,26,28H2,1-6H3,(H,52,66)(H,58,64)(H,59,67)(H,53,55,56,57)/t35-,37+,45-/m1/s1
Chemical Name	N-(2-chloro-6-methylphenyl)-2-[[6-[4-[8-[[(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]amino]-8-oxooctanoyl]piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide
Synonyms	SIAIS178 SIAIS-178
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	In a concentration-dependent manner, SIAIS178 (1-100 nM) dramatically decreased BCR-ABL protein levels throughout a 16-hour period. The phosphorylation of BCR-ABL and its substrate STAT5 is strongly inhibited by SIAIS178 [1]. It has been observed that SIAIS178 (1, 10, 100, and 1000 nM) significantly inhibits the proliferation of BCR-ABL-driven CML cell lines. When used against BCR-ABL driven cell lines, SIAIS178 maintains its efficacy and selectivity [1].
ln Vivo	SIAIS178 (ip; 5, 15 and 45 mg/kg; 12 days) attenuates tumor development in a dose-dependent manner as demonstrated by serial volume assessments [1]. SIAIS178 (intravenous or intraperitoneal injection; 2 mg/kg; 24 hours) exhibits a T1/2 of 3.82 hours and 12.35 hours, with a Cmax of 1165.2 nM and 30 nM for intravenous and intraperitoneal administration, respectively [1].
Cell Assay	Western Blot Analysis[1] Cell Types: K562 Cell Tested Concentrations: 1, 3, 10, 30, 100 nM Incubation Duration: 16 hrs (hours) Experimental Results: Dramatically diminished BCR-ABL protein levels in a concentration-dependent manner.
Animal Protocol	Animal/Disease Models: Female Wistar rat [1] Doses: 2 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)injection or intraperitoneal (ip) injection; 24-hour Experimental Results: T1/2 of intravenous (iv) (iv)injection and intraperitoneal (ip) injection are respectively 3.82 and 12.35 hrs (hrs (hours)), Cmax were 1165.2 nM and 30 nM respectively.
References	[1]. Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase. J Med Chem. 2019 Oct 24;62(20):9281-9298.

Solubility Data

Solubility (In Vitro)

DMSO : ~300 mg/mL (~296.24 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 7.5 mg/mL (7.41 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 75.0 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	0.9875 mL	4.9374 mL	9.8748 mL
	5 mM	0.1975 mL	0.9875 mL	1.9750 mL
	10 mM	0.0987 mL	0.4937 mL	0.9875 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.