Onc-206
[CAS# 1638178-87-6]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein)
• Name: Onc-206
• Synonyms: 11-benzyl-7-[(2,4-difluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one
• Molecular Formula: C₂₃H₂₂F₂N₄O
• Molecular Weight: 408.44
• CAS Registry Number: 1638178-87-6
• SMILES: C1CN(CC2=C1N3CCN=C3N(C2=O)CC4=C(C=C(C=C4)F)F)CC5=CC=CC=C5

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319
• Safety Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovery and Applications

ONC-206 is an investigational small molecule compound under development for the treatment of central nervous system (CNS) and solid tumors. It is a derivative of the imipridone class, which includes ONC201, and is being studied for its dual-targeted mechanism of action.

The compound functions as a selective antagonist of the dopamine D2-like receptors (DRD2, DRD3, and DRD4) and as an agonist of the mitochondrial caseinolytic protease (ClpP). By engaging these targets, ONC-206 induces mitochondrial dysfunction, activation of the integrated stress response, and inhibition of pro-survival Ras signaling pathways, leading to tumor cell death.

ONC-206 has demonstrated efficacy in preclinical models of difficult-to-treat CNS tumors, such as high-grade gliomas and medulloblastomas, as well as non-CNS solid tumors, including neuroendocrine, breast, and endometrial cancers. It is administered orally and has shown favorable pharmacokinetic properties, including blood-brain barrier penetration.

Clinical trials are underway to evaluate the safety and efficacy of ONC-206 in patients with newly diagnosed or recurrent diffuse midline gliomas and other primary malignant CNS tumors. Early-phase studies have indicated that ONC-206 is well-tolerated at doses that achieve therapeutic exposures.

In summary, ONC-206 is a promising dual-targeted agent with potential applications in the treatment of various malignancies, particularly those of the CNS. Its unique mechanism of action and favorable pharmacological profile support its continued development in clinical settings.

References

2022. Induction of Synthetic Lethality by Activation of Mitochondrial ClpP and Inhibition of HDAC1/2 in Glioblastoma. Clinical Cancer Research, 28(4).
DOI: 10.1158/1078-0432.CCR-21-2857

2024. ONC206 targeting ClpP induces mitochondrial dysfunction and protective autophagy in hepatocellular carcinoma cells. Neoplasia, 55.
DOI: 10.1016/j.neo.2024.101015