Name: CP-10
Brand: BOC Sciences
Rating: 5 (1 reviews)

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IUPACName

4-[2-[2-[4-[[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]pyridin-3-yl]piperazin-1-yl]methyl]triazol-1-yl]ethoxy]ethylamino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

Synonyms

CDK6 degrader CP-10; 4-((2-(2-(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)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 1H-Isoindole-1,3(2H)-dione, 4-[[2-[2-[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]methyl]-1H-1,2,3-triazol-1-yl]ethoxy]ethyl]amino]-2-(2,6-dioxo-3-piperidinyl)-; 4-[[2-[2-[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]methyl]-1H-1,2,3-triazol-1-yl]ethoxy]ethyl]amino]-2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione

Density

1.55±0.1 g/cm3

InChI Key

PACRWHUPEPCFHX-UHFFFAOYSA-N

InChI

InChI=1S/C44H49N13O7/c1-26-32-23-47-44(50-39(32)56(29-6-3-4-7-29)42(62)37(26)27(2)58)48-35-12-10-30(22-46-35)54-17-15-53(16-18-54)24-28-25-55(52-51-28)19-21-64-20-14-45-33-9-5-8-31-38(33)43(63)57(41(31)61)34-11-13-36(59)49-40(34)60/h5,8-10,12,22-23,25,29,34,45H,3-4,6-7,11,13-21,24H2,1-2H3,(H,49,59,60)(H,46,47,48,50)

SMILES

CC1=C(C(=O)N(C2=NC(=NC=C12)NC3=NC=C(C=C3)N4CCN(CC4)CC5=CN(N=N5)CCOCCNC6=CC=CC7=C6C(=O)N(C7=O)C8CCC(=O)NC8=O)C9CCCC9)C(=O)C

Mechanism

Target: CP-10 preferentially targets CDK6, with weaker degradation activity toward CDK4.

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

Mechanism of action: CP-10 is a CRBN-recruiting CDK6 PROTAC generated by linking a CDK4/6 ligand to a pomalidomide-derived cereblon ligand. Although its recognition element can engage both CDK4 and CDK6, CP-10 displays markedly stronger degradation of CDK6, enabling selective depletion of wild-type, overexpressed, or mutant CDK6 in cellular systems. This event-driven mechanism promotes CDK6 ubiquitination and proteasome-mediated clearance, supporting studies of cell-cycle control, hematopoietic cancer cell models, CDK4 versus CDK6 functional separation, and phenotypic differences between kinase inhibition and protein degradation.

Applications

• Protac-Mediated Kinase Degradation: CP-10 is utilized in research to specifically target and degrade kinase proteins, offering a novel approach to study kinase signaling pathways. This application aids in dissecting the role of kinases in cellular processes and disease mechanisms through selective protein knockdown.

• Targeted Degradation in Cancer Research: CP-10 facilitates the selective degradation of oncogenic proteins within cancer cells, providing a powerful tool for elucidating cancer biology. By enabling the removal of specific proteins, researchers can explore potential vulnerabilities and therapeutic targets in tumor progression.

• Protein Homeostasis Studies: Utilizing CP-10 in experiments allows researchers to investigate the impact of targeted protein degradation on cellular protein homeostasis. This application is critical for understanding the dynamics of protein turnover and the cellular response to proteome alterations.

• Neurodegenerative Disease Modeling: CP-10 is applied to degrade aberrant proteins implicated in neurodegenerative diseases, offering insights into disease pathogenesis. By simulating protein clearance mechanisms, researchers can study neuroprotective strategies and potential therapeutic interventions.

1. Potent and preferential degradation of CDK6 via proteolysis targeting chimera degraders.

Su, S., Yang, Z., Gao, H., Yang, H., Zhu, S., An, Z., Wang, J., Li, Q., Chandarlapaty, S., Deng, H. and Wu, W., 2019. Journal of medicinal chemistry, 62(16), pp.7575-7582.

A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.

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