Name: BSJ-03-204
Brand: BOC Sciences
Rating: 5 (1 reviews)

Purity

≥98%

Solubility

In DMSO: 100 mg/mL (120.06 mM; Need ultrasonic)

Appearance

Solid Powder

Storage

-20°C, protect from light; In solvent, -80°C, 6 months; -20°C, 1 month (protect from light)

Shipping

Room temperature in continental US; may vary elsewhere.

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]oxyacetamide

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)oxy)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]oxy]-; 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]oxy]acetamide; BSJ-03204; BSJ03204; BSJ 03 204

Density

1.397±0.06 g/cm3

InChI Key

KDMOCOWXLQOXEB-UHFFFAOYSA-N

InChI

InChI=1S/C43H48N10O8/c1-25-30-23-46-43(49-38(30)52(27-8-3-4-9-27)41(59)36(25)26(2)54)47-33-14-12-28(22-45-33)51-20-18-50(19-21-51)17-6-5-16-44-35(56)24-61-32-11-7-10-29-37(32)42(60)53(40(29)58)31-13-15-34(55)48-39(31)57/h7,10-12,14,22-23,27,31H,3-6,8-9,13,15-21,24H2,1-2H3,(H,44,56)(H,48,55,57)(H,45,46,47,49)

SMILES

CC(=O)C1=C(C)C2=CN=C(NC3=CC=C(N4CCN(CCCCNC(=O)COC5=CC=CC6=C5C(=O)N(C5CCC(=O)NC5=O)C6=O)CC4)C=N3)N=C2N(C2CCCC2)C1=O

Mechanism

Target: BSJ-03-204 targets cyclin-dependent kinases CDK4 and CDK6 for degradation.

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

Mechanism of action: BSJ-03-204 is a palbociclib-based CDK4/6 dual PROTAC that recruits cereblon to promote degradation of CDK4 and CDK6. The compound connects a CDK4/6-recognition ligand to a CRBN ligand, enabling ternary-complex formation and ubiquitin-proteasome-dependent target depletion. Reported activity includes potent biochemical engagement of CDK4/cyclin D1 and CDK6/cyclin D1 and selective degradation without inducing IKZF1/3 loss. BSJ-03-204 is useful for studying G1 cell-cycle control, CDK4 versus CDK6 contribution, RB pathway regulation, and differences between CDK4/6 inhibition and protein degradation.

Applications

• PROTAC-Mediated Kinase Degradation: BSJ-03-204 serves as a potent tool for the selective degradation of kinases, enabling researchers to study kinase signaling pathways by removing specific kinase proteins. This facilitates a deeper understanding of kinase roles in cellular processes and disease mechanisms, offering insights into potential therapeutic targets.

• Targeted Protein Degradation in Oncology: Utilizing BSJ-03-204, researchers can explore the degradation of oncogenic proteins, providing a unique approach to investigate cancer biology. This application aids in identifying critical proteins involved in tumor growth and survival, potentially revealing novel intervention points for cancer treatment.

• Mechanistic Studies of Protein Turnover: BSJ-03-204 allows scientists to investigate the dynamics of protein turnover within cells. By targeting specific proteins for degradation, researchers can elucidate the mechanisms governing protein stability and degradation, contributing to a broader comprehension of cellular homeostasis.

• Functional Genomics via PROTAC: BSJ-03-204 is employed in functional genomics studies to selectively degrade proteins of interest. This approach aids in determining protein function and interaction networks, offering valuable data for constructing detailed cellular models and understanding complex biological systems.

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. Development of dual and selective degraders of cyclin-dependent kinases 4 and 6.

Jiang, B., Wang, E.S., Donovan, K.A., Liang, Y., Fischer, E.S., Zhang, T. and Gray, N.S., 2019. Angewandte Chemie International Edition, 58(19), pp.6321-6326.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there are FDA-approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation of their ATP-binding sites, development of selective agents has remained elusive. Here, we report imide-based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), which are well-established targets of imide-based degraders. We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti-proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In summary, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
0.2 mM	6 mL	30.01 mL	60.03 mL
1 mM	1.2 mL	6 mL	12.01 mL
2 mM	0.6 mL	3 mL	6 mL
10 mM	0.12 mL	0.6 mL	1.2 mL

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* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂