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| Targets |
BCR-ABL fusion protein, and E3 ubiquitin ligase (VHL). SIAIS178 is a heterobifunctional PROTAC molecule that simultaneously binds to BCR-ABL (via the kinase domain ligand) and the E3 ubiquitin ligase VHL. By bringing the target protein and the ligase into close proximity, it induces the ubiquitination of BCR-ABL. This tags the BCR-ABL protein for recognition and degradation by the proteasome. The IC₅0 for BCR-ABL degradation is 24 nM. SIAIS178 also degrades several clinically relevant, drug-resistant BCR-ABL mutants.
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| 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].
In vitro, SIAIS178 achieves significant growth inhibition of BCR-ABL+ leukemic cells (e.g., K562 cells). It effectively degrades the BCR-ABL protein in a dose-dependent manner, with an IC₅0 of 24 nM. The compound induces proper interaction between BCR-ABL and the VHL ligase, leading to effective and selective degradation of the oncoprotein. This degradation results in potent anti-proliferative effects and induces apoptosis in CML cell lines, including those resistant to first-line TKIs. |
| 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].
In vivo, SIAIS178 demonstrates substantial anti-tumor activity in a K562 xenograft mouse model of CML. Using NOD/SCID mice bearing K562-Luc tumors, SIAIS178 is administered at doses of 5, 15, and 45 mg/kg. It attenuates tumor progression in a dose-dependent manner and induces substantial tumor regression. The in vivo efficacy correlates with the degradation of BCR-ABL within the tumor tissue, confirming that the PROTAC mechanism is operational in a physiological context and can significantly reduce disease burden. |
| Enzyme Assay |
A cell-free ubiquitination assay is conducted. Recombinant VHL-Elongin B-Elongin C (VBC) complex, E1 ubiquitin-activating enzyme, E2 conjugating enzyme, ubiquitin, and BCR-ABL kinase domain protein are mixed in a reaction buffer. SIAIS178 is added to the reaction. The mixture is incubated at 30degC for 60-120 minutes. The reaction is stopped with SDS loading buffer, and the samples are analyzed by Western blot using an antibody against ubiquitin (FK2) to detect high molecular weight poly-ubiquitinated BCR-ABL smears.
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| 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. K562 human CML cells (BCR-ABL+) are seeded in 6-well plates and treated with increasing concentrations of SIAIS178 (0.001-1 microM) for 24 hours. Cells are collected, lysed in RIPA buffer containing protease inhibitors, and protein concentration is normalized. Lysates are resolved by SDS-PAGE and transferred to PVDF membranes. Membranes are immunoblotted with anti-BCR-ABL (c-Abl) antibody and anti-beta-actin as a loading control. The DC₅0 (concentration for 50% degradation) is determined by densitometry analysis of the Western blot bands. Cell viability is assessed by CCK-8 or MTT assay. |
| 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. In vivo, a K562-Luc xenograft model is used in NOD/SCID mice. A total of 5 × 10⁶ K562-Luc cells are injected subcutaneously into the right flank of mice. When tumors reach an average volume of 100-150 mm3, mice are randomized (n=6-8 per group). SIAIS178 is formulated in a vehicle (e.g., 10% DMSO in 90% corn oil) and administered intraperitoneally or intravenously at 5, 15, 45 mg/kg once daily. Tumor progression is monitored via bioluminescence imaging using an IVIS system 10-15 minutes after luciferin injection. Tumor volumes are also measured with calipers twice weekly. Body weight is measured as an indicator of toxicity. |
| ADME/Pharmacokinetics |
Specific PK data for SIAIS178 is not detailed in the search results. As a PROTAC, its molecular weight is 1012.68 g/mol, which is significantly larger than traditional small molecules. This may result in poor oral bioavailability, though it is soluble in DMSO (300 mg/mL). It is likely suitable for systemic administration via intraperitoneal (i.p.) or intravenous (i.v.) injection. Metabolic stability in liver microsomes and plasma half-life (t1/2) would need to be determined to optimize dosing regimens. Standard research storage is as a solid powder.
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| Toxicity/Toxicokinetics |
No acute or chronic toxicology data is reported for SIAIS178. As a BCR-ABL degrader, its on-target activity aims to specifically eliminate leukemic cells. However, there is a potential risk of off-target degradation of other proteins containing similar binding motifs. In xenograft studies, the compound was well-tolerated at effective doses, but standard toxicological endpoints (weight loss, tissue histology, serum chemistry) would require further investigation. Standard safety precautions for handling research chemicals should be followed.
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| References | |
| Additional Infomation |
SIAIS178 is a PROTAC research compound and is not an FDA-approved drug. It has not yet entered clinical trials for CML. It is a novel degrader distinct from traditional inhibitors, offering a pathway to overcome drug resistance caused by point mutations in the BCR-ABL kinase domain. Its discovery highlights the potential of PROTAC technology for the treatment of hematological malignancies. It is a valuable tool for studying the biology of BCR-ABL and for validating degradation as a therapeutic strategy.
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| Molecular Formula |
C50H62CLN11O6S2
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|---|---|
| Molecular Weight |
1012.68038702011
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| Exact Mass |
1011.401
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| CAS # |
2376047-73-1
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| PubChem CID |
139474625
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| Appearance |
White to off-white solid powder
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| LogP |
7.5
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
19
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| Heavy Atom Count |
70
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| Complexity |
1750
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| Defined Atom Stereocenter Count |
3
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| 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
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| InChi Key |
YGQREOJIRFCRKQ-ZIBKGDFVSA-N
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| 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
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| 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
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| Synonyms |
SIAIS178 SIAIS-178
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ~300 mg/mL (~296.24 mM)
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| 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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