Name: SIAIS178
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥99%

Solubility

Soluble in DMSO (300 mg/mL, 296.24 mM, Need ultrasonic)

Appearance

Solid Powder

Storage

Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)

IUPACName

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

SIAIS 178; SIAIS-178; N-(2-Chloro-6-methylphenyl)-2-((6-(4-(8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methyl-thiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; N-(8-{4-[6-({5-[(2-Chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methyl-4-pyrimidinyl]-1-piperazinyl}-8-oxooctanoyl)-3-methyl-L-valyl-(4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)benzyl]-L-prolinamide

Density

1.335±0.06 g/cm3

InChI Key

YGQREOJIRFCRKQ-ZIBKGDFVSA-N

InChI

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

SMILES

CC1=C(C(=CC=C1)Cl)NC(=O)C2=CN=C(S2)NC3=CC(=NC(=N3)C)N4CCN(CC4)C(=O)CCCCCCC(=O)NC(C(=O)N5CC(CC5C(=O)NCC6=CC=C(C=C6)C7=C(N=CS7)C)O)C(C)(C)C

Mechanism

Target: SIAIS178 targets the oncogenic BCR-ABL fusion tyrosine kinase protein.

Binding site: Its kinase ligand binds the ATP-binding catalytic cleft of BCR-ABL.

Mechanism of action: SIAIS178 is a VHL-recruiting PROTAC designed to induce selective degradation of BCR-ABL rather than simply inhibit its kinase activity. The molecule couples a BCR-ABL-recognition ligand to a von Hippel-Lindau E3 ligase ligand, enabling ternary-complex formation between BCR-ABL and the CUL2VHL ubiquitin ligase system. This proximity promotes ubiquitination and proteasome-dependent depletion of the fusion protein, supporting sustained suppression of BCR-ABL-driven signaling. In research settings, SIAIS178 is useful for studying degradation-based modulation of tyrosine kinase signaling, resistance-associated protein persistence, and target removal versus catalytic inhibition.

Applications

• PROTAC-Mediated Kinase Degradation: SIAIS178 is utilized in the targeted degradation of specific kinase proteins, providing researchers with a powerful tool to study kinase signaling pathways and their roles in cellular processes. This application enables the exploration of therapeutic targets by selectively degrading kinases implicated in various diseases.

• Targeted Protein Degradation in Oncology: SIAIS178 facilitates the degradation of oncogenic proteins, offering a novel approach to investigate cancer biology. By degrading proteins that drive tumor growth and survival, researchers can gain insights into cancer mechanisms and identify potential therapeutic strategies.

• Investigating Protein-Protein Interactions: Using SIAIS178, scientists can study the effects of degrading specific proteins involved in protein-protein interactions. This application provides a deeper understanding of cellular networks and the consequences of disrupting these interactions, which is crucial for drug discovery and development.

• PROTAC-Based Neurodegenerative Research: SIAIS178 aids in the targeted degradation of proteins associated with neurodegenerative diseases. Researchers can utilize this approach to dissect the pathological roles of these proteins, advancing the development of treatments for conditions such as Alzheimer's and Parkinson's diseases.

1. Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase

Yubao Shao, Quanju Zhao, Chaowei Ren, Renhong Sun, Xinyu Ding, Bei Yang, Ying Kong, Xianfang Zhang, Youwei Xu, Biao Jiang, Xiaobao Yang, Jinju Chen, Ning Sun, Qianqian Yin, Linyi Liu J Med Chem . 2019 Oct 24;62(20):9281-9298. doi: 10.1021/acs.jmedchem.9b01264.

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite great progress for CML treatment through application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, long-term drug administration and clinical resistance continue to be an issue. Herein, we described the design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers. Our efforts have yielded SIAIS178 (19), which induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL+leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAIS178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL+leukemia.

Good afternoon, what is the mechanism of action of SIAIS178?

SIAIS178 utilizes a technology called PROTAC (proteolysis targeting chimera). It functions as a "molecular glue," linking BCR-ABL to E3 ubiquitin ligases, cellular machinery responsible for protein degradation. This binding initiates the ubiquitination of BCR-ABL, marking it for destruction by the proteasome, the cell's protein degradation system.

12/1/2019

Hello, what is its activity as Potent and Selective BCR-ABL Degrader?

SIAIS178 exhibits potent activity against BCR-ABL with an IC50 of 24 nM. This low value indicates it only requires a small amount to significantly reduce BCR-ABL protein levels. It acts selectively towards BCR-ABL, meaning it primarily targets this protein and minimizes off-target effects on other proteins.

16/1/2019

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