Name: MS4077
Brand: BOC Sciences
Rating: 5 (1 reviews)

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Solubility

10 mM in DMSO

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

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Room temperature in continental US; may vary elsewhere

Synonyms

MS4077; MS 4077; MS-4077; 2-[4-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-2-methyl-5-propan-2-yloxyphenyl]piperidin-1-yl]-N-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide

InChI Key

VEKJQNCZEPLNJF-UHFFFAOYSA-N

InChI

InChI=1S/C55H72ClN9O13S/c1-35(2)78-46-32-40(37(5)31-44(46)61-55-59-33-41(56)51(63-55)60-42-10-6-7-12-47(42)79(71,72)36(3)4)38-15-19-64(20-16-38)34-49(67)58-18-22-74-24-26-76-28-30-77-29-27-75-25-23-73-21-17-57-43-11-8-9-39-50(43)54(70)65(53(39)69)45-13-14-48(66)62-52(45)68/h6-12,31-33,35-36,38,45,57H,13-30,34H2,1-5H3,(H,58,67)(H,62,66,68)(H2,59,60,61,63)

SMILES

CC1=CC(=C(C=C1C2CCN(CC2)CC(=O)NCCOCCOCCOCCOCCOCCNC3=CC=CC4=C3C(=O)N(C4=O)C5CCC(=O)NC5=O)OC(C)C)NC6=NC=C(C(=N6)NC7=CC=CC=C7S(=O)(=O)C(C)C)Cl

Mechanism

Target: MS4077 targets anaplastic lymphoma kinase, including oncogenic ALK fusion proteins.

Binding site: Its ceritinib-derived warhead binds the ATP pocket of the ALK kinase domain.

Mechanism of action: MS4077 is a CRBN-recruiting ALK PROTAC designed to induce degradation of oncogenic ALK fusion proteins rather than only inhibit kinase activity. The compound links an ALK-binding moiety to a cereblon ligand, enabling ternary-complex formation with CRL4CRBN and subsequent ubiquitination of ALK. Proteasome-dependent depletion reduces ALK autophosphorylation and downstream STAT3 signaling in ALK-driven cellular models. This degradation-based approach supports studies of fusion kinase dependency, target residence versus protein removal, signaling durability, and concentration-dependent degradation behavior in targeted protein degradation experiments.

Applications

• PROTAC-Mediated Kinase Degradation: MS4077 is utilized to selectively degrade kinases involved in signaling pathways, providing researchers with a powerful tool to dissect kinase functions and investigate their roles in cellular processes. This approach aids in elucidating mechanisms of disease and identifying potential therapeutic targets.

• Targeted Degradation of Oncoproteins: By employing MS4077, researchers can achieve specific degradation of oncoproteins implicated in cancer progression. This facilitates the study of oncogenic pathways and supports the development of strategies for targeted cancer therapy through the precise elimination of disease-driving proteins.

• PROTAC-Based Neurodegenerative Research: MS4077 is instrumental in investigating the degradation of proteins associated with neurodegenerative disorders. By enabling targeted protein degradation, it offers a novel method to explore protein homeostasis and its impact on neuronal health, contributing to the understanding of disease mechanisms.

• Degradation of E3 Ligase Substrates: Utilizing MS4077 allows for the targeted degradation of substrates recognized by specific E3 ligases. This application is pivotal in studying the ubiquitin-proteasome system and its regulatory roles in various cellular processes, advancing our comprehension of protein turnover and stability.

1. Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK)

Chengwei Zhang, Xiao-Ran Han, Xiaobao Yang, Biao Jiang, Jing Liu, Yue Xiong, Jian Jin Eur J Med Chem. 2018 May 10;151:304-314. doi: 10.1016/j.ejmech.2018.03.071.Epub 2018 Mar 27.

Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5-8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs.

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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂