MODEYSO is a targeted treatment and the first of its kind1

By targeting oncogenic pathways, MODEYSO reverses H3 K27me3 loss, the central hallmark of H3 K27M–mutant diffuse midline glioma2,3

MECHANISM OF MODEYSO

As a CNS-penetrant protease activator, MODEYSO addresses the epigenetic dysregulation and pathway activation1,2,4,5

Protease activators are a class of small-molecule anticancer compounds that share a unique heterocyclic pharmacophore that targets specific GPCRs and mitochondrial ClpP, resulting in cancer cell death.1,4

  1. Allosteric agonist of the mitochondrial ClpP protease unit: MODEYSO binds to ClpP at specific sites, altering energy production and inducing a stress response that leads to tumor cell apoptosis.1,2,4,5

MODEYSO binding to the mitochondrial caseinolytic protease P enzyme.

  1. Antagonist of the dopamine receptor D2 (DRD2): MODEYSO targets DRD2 to decrease the activation of key oncogenic signaling pathways for tumor growth.1,2,4,5

MODEYSO inhibiting the dopamine D2 receptor

Watch the MODEYSO mechanism of action video

 Learn more about how MODEYSO penetrates the blood-brain barrier to target tumor cells.1

In cell-based assays and in vivo models of H3 K27M–mutant diffuse glioma, MODEYSO exhibited antitumor activity. Altered mitochondrial metabolism induced by MODEYSO impacts histone demethylases to reverse H3 K27me3 loss2

ClpP, caseinolytic protease P; CNS, central nervous system; DRD2, dopamine receptor D2; GPCRs, G protein-coupled receptors; H3, histone 3; K, lysine; M, methionine; me, methyl.

Explore efficacy results from the integrated analysis

References: 1. Allen JE, Kline CL, Prabhu VV, et al. Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget. 2016;7(45):74380-74392. doi:10.18632/oncotarget.11814 2. MODEYSO™. Package insert. Jazz Pharmaceuticals, Inc; 2026. 3. Saratsis AM, Knowles T, Petrovic A, Nazarian J. H3K27M mutant glioma: disease definition and biological underpinnings. Neuro Oncol. 2024;26(suppl 2):S92-S100. doi:10.1093/neuonc/noad164 4. Free RB, Cuoco CA, Xie B, et al. Pharmacological characterization of the imipridone anticancer drug ONC201 reveals a negative allosteric mechanism of action at the D2 dopamine receptor. Mol Pharmacol. 2021;100(4):372-387. doi:10.1124/molpharm.121.000336 5. Jackson ER, Persson ML, Fish CJ, et al. A review of current therapeutics targeting the mitochondrial protease ClpP in diffuse midline glioma, H3 K27-altered. Neuro Oncol. 2024;26(suppl 2):S136-S154. doi:10.1093/neuonc/noad144