Dordaviprone
A protease inhibitor used to treat diffuse midline glioma with a H3 K27M mutation.
Overview
Dordaviprone is a first-in-class small molecule imipridone. It is used to treat patients with diffuse midline glioma harboring an H3 K27M mutation. Dordaviprone was initially studied as an anticancer agent that induces TNF-Related Apoptosis-Inducing Ligand (TRAIL). Dordaviprone has several modes of action, including the activation of mitochondrial caseinolytic protease P (ClpP), antagonism of the dopamine D2 receptor,5 activation of Activating Transcription Factor 4 (ATF4), and induction of endoplasmic reticulum (ER) stress response.
Synonyms: NSC-350625; TIC-10; ONC-201; ONC201; OP-10; Modeyso; TRAIL-inducing compound 10 (Oncoceutics); 2,4,6,7,8,9-Hexahydro-4-((2-methylphenyl)methyl)-7-phenylmethyl)imidazo)(1,2-a)pyrido(3,4-e)pyrimidin-5(1H)-one; 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo(1,2-A)pyrido(3,4-E)pyrimidin-5(4H)-one
Product Categories: Antineoplastic Agents; Cytochrome P-450 CYP3A4 Substrates; Cytochrome P-450 CYP2B6 Substrates; Cytochrome P-450 CYP2C8 Substrates; Cytochrome P-450 CYP2C9 Substrates; Cytochrome P-450 CYP2D6 Substrates; Cytochrome P-450 CYP3A5 Substrates; Cytochrome P-450 Substrates; QTc Prolonging Agents
Mol File: 1616632-77-9.mol
Physicochemical Properties
Boiling point: 559.7±60℃
Storage temp: Sealed in dry,Store in freezer, under -20°C
Solubility: Soluble in DMSO (up to 25 mg/ml at elevated temperatures)
Form: Solid
Color: Pale Yellow
Stability: Solutions in DMSO are stable for 2 months when stored at -20°C
MSDS Information
Experimental Data
Pharmacodynamics
Dordaviprone is a drug with anti-tumour activity: It exhibited anti-tumour activity in cell-based assays and in vivo models of H3 K27M-mutant diffuse glioma. Dordaviprone causes a concentration-dependent QTc interval prolongation. At 1.2 times the maximum recommended dose, the estimated mean QTcF change was 11.8 msec (90% CI: 9.8, 13.7). The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of dordaviprone have not been fully characterized.
Mechanism Of Action
Dordaviprone is a protease activator of the mitochondrial caseinolytic protease P (ClpP), a mitochondrial serine protease. Diffuse midline gliomas harboring an H3 K27M mutation are associated with the loss of H3 K27 trimethylation. In vitro, dordaviprone induced apoptosis and altered mitochondrial metabolism leading to restored histone H3 K27 trimethylation in H3 K27M-mutant diffuse glioma models. Dordaviprone activates ATF4 and induces endoplasmic reticulum (ER) stress response or integrated stress response (ISR). Dordaviprone also inhibits the dopamine D2 receptor, which are often overexpressed in multiple cancers, including glioblastoma.
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