Name: BSJ-02-162
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Storage

Store at -20°C

IUPACName

N-[4-[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]pyridin-3-yl]piperazin-1-yl]butyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]acetamide

Synonyms

N-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)butyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide; Acetamide, N-[4-[4-[6-[(6-acetyl-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]-3-pyridinyl]-1-piperazinyl]butyl]-2-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]-; N-[4-[4-[6-[(6-Acetyl-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]-3-pyridinyl]-1-piperazinyl]butyl]-2-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]acetamide; CDK4/6-IN-11

Density

1.406±0.06 g/cm3

InChI Key

AWPNCYPNCSCZFL-UHFFFAOYSA-N

InChI

InChI=1S/C43H49N11O7/c1-25-30-23-47-43(50-38(30)53(27-8-3-4-9-27)41(60)36(25)26(2)55)48-33-14-12-28(22-46-33)52-20-18-51(19-21-52)17-6-5-16-44-35(57)24-45-31-11-7-10-29-37(31)42(61)54(40(29)59)32-13-15-34(56)49-39(32)58/h7,10-12,14,22-23,27,32,45H,3-6,8-9,13,15-21,24H2,1-2H3,(H,44,57)(H,49,56,58)(H,46,47,48,50)

SMILES

CC(=O)C1=C(C)C2=CN=C(NC3=CC=C(N4CCN(CCCCNC(=O)CNC5=CC=CC6=C5C(=O)N(C5CCC(=O)NC5=O)C6=O)CC4)C=N3)N=C2N(C2CCCC2)C1=O

Mechanism

Target: BSJ-02-162 targets CDK4 and CDK6, with associated IKZF1/3 degradation risk.

Binding site: Its palbociclib-derived ligand binds ATP-competitive catalytic pockets of CDK4/6.

Mechanism of action: BSJ-02-162 is a cereblon-recruiting CDK4/6 PROTAC constructed from palbociclib, a linker, and a thalidomide-derived CRBN ligand. By recruiting CDK4 and CDK6 to CRL4CRBN ubiquitin ligase machinery, it promotes ubiquitination and proteasome-dependent degradation of cell-cycle kinases. Because CRBN-based designs may also affect neosubstrates such as IKZF1 and IKZF3, experimental interpretation should monitor both intended CDK degradation and CRBN neosubstrate effects. BSJ-02-162 is useful for studying RB pathway regulation, CDK paralog function, cell-cycle arrest, and degrader-versus-inhibitor pharmacology.

Applications

• PROTAC-Mediated Kinase Degradation: BSJ-02-162 is designed to selectively degrade specific kinases involved in signaling pathways. By facilitating the ubiquitination and proteasomal degradation of target kinases, this PROTAC can help elucidate the roles of these enzymes in cellular processes, providing insights into kinase-driven diseases.

• Targeted Degradation in Cancer Research: Utilizing BSJ-02-162 allows researchers to investigate the therapeutic potential of degrading oncogenic proteins. This approach aids in studying the effects of targeted protein degradation on cancer cell viability, offering a promising strategy for developing targeted cancer therapies.

• Ubiquitin-Proteasome System Exploration: BSJ-02-162 serves as a tool to probe the ubiquitin-proteasome system's function in protein homeostasis. By promoting the degradation of specific proteins, researchers can better understand the dynamics of protein turnover and its implications in various diseases.

• PROTAC-Based Drug Discovery: BSJ-02-162 is instrumental in the discovery and validation of new drug targets through targeted protein degradation. This PROTAC enables the identification of essential proteins in disease pathways, facilitating the development of novel therapeutic strategies.

1. Mapping the degradable kinome provides a resource for expedited degrader development.

Donovan, K.A., Ferguson, F.M., Bushman, J.W., Eleuteri, N.A., Bhunia, D., Ryu, S., Tan, L., Shi, K., Yue, H., Liu, X. and Dobrovolsky, D., 2020. Cell, 183(6), pp.1714-1731.

Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ~200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.

2. Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.

Anderson, N.A., Cryan, J., Ahmed, A., Dai, H., McGonagle, G.A., Rozier, C. and Benowitz, A.B., 2020. Bioorganic & Medicinal Chemistry Letters, 30(9), p.127106.

Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.

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