Name: INY-03-041
Brand: BOC Sciences
Rating: 5 (1 reviews)

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IUPACName

3-[7-[10-[[(2S)-2-(4-chlorophenyl)-3-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl]-3-oxopropyl]amino]decyl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione

Synonyms

3-(4-(10-(((S)-2-(4-Chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)decyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Boiling Point

997.6±65.0°C at 760 Torr

Density

1.273±0.06 g/cm3

InChI Key

GQGZWBDNMCIYSF-OZDCPDTESA-N

InChI

InChI=1S/C44H56ClN7O5/c1-29-25-37(53)40-39(29)41(48-28-47-40)50-21-23-51(24-22-50)43(56)34(31-14-16-32(45)17-15-31)26-46-20-9-7-5-3-2-4-6-8-11-30-12-10-13-33-35(30)27-52(44(33)57)36-18-19-38(54)49-42(36)55/h10,12-17,28-29,34,36-37,46,53H,2-9,11,18-27H2,1H3,(H,49,54,55)/t29-,34-,36?,37-/m1/s1

SMILES

O=C1NC(=O)C(N2C(=O)C3=CC=CC(=C3C2)CCCCCCCCCCNCC(C(=O)N4CCN(C5=NC=NC6=C5C(C)CC6O)CC4)C7=CC=C(Cl)C=C7)CC1

Mechanism

Target: INY-03-041 targets pan-AKT kinases, including AKT1, AKT2, and AKT3 isoforms.

Binding site: Its GDC-0068 warhead binds the ATP-competitive catalytic pocket of AKT kinases.

Mechanism of action: INY-03-041 is a bifunctional PROTAC that couples an ATP-site AKT ligand derived from GDC-0068/ipatasertib to lenalidomide, enabling recruitment of the CRBN E3 ubiquitin ligase. By simultaneously engaging AKT and CRBN, it promotes productive ternary-complex formation, AKT polyubiquitination, and proteasome-dependent depletion of AKT1/2/3 rather than transient enzymatic blockade. In cellular degradation studies, this pan-AKT degrader supports evaluation of PI3K/AKT pathway dependence, duration of downstream signaling suppression, isoform contribution, and concentration-dependent hook effects that can influence dose selection in targeted protein degradation experiments.

Applications

• PROTAC-Mediated Kinase Degradation: AK-2292 is designed to facilitate the selective degradation of specific kinase proteins, thereby providing researchers a powerful tool to study kinase signaling pathways and their roles in disease mechanisms. This approach allows for the exploration of kinase function by transiently removing the protein from cellular systems.

• Targeted Degradation in Oncology Research: By employing AK-2292, scientists can investigate the degradation of oncogenic proteins, offering insights into the potential vulnerabilities of cancer cells. This targeted approach aids in understanding protein dependencies and could guide the development of novel therapeutic strategies.

• Exploring Protein-Protein Interactions: AK-2292 enables the study of protein-protein interactions by selectively degrading target proteins involved in complex cellular networks. This application is crucial for dissecting the dynamic roles of proteins and their interactions in various biological processes.

• Advancing Neurodegenerative Disease Models: Utilizing AK-2292, researchers can target and degrade proteins implicated in neurodegenerative diseases. This helps in elucidating the pathological roles of these proteins and provides a platform for developing potential therapeutic interventions.

1. Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling

Katherine A Donovan, Nathanael S Gray, Alex Toker, Emily C Erickson, Eric S Fischer, Inchul You, Nicholas A Eleuteri Cell Chem Biol . 2020 Jan 16;27(1):66-73.e7. doi: 10.1016/j.chembiol.2019.11.014.

The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half of tumors exhibiting aberrant AKT activation. Although potent small-molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of the ATP-competitive AKT inhibitor GDC-0068 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 h, even after compound washout. Our findings suggest that AKT degradation may confer prolonged pharmacological effects compared with inhibition, and highlight the potential advantages of AKT-targeted degradation.

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