ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

Abstract

ONC201 was originally discovered as TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound TIC10. ONC201 appears to act as a selective antagonist of the G protein coupled receptor (GPCR) dopamine receptor D2 (DRD2), and as an allosteric agonist of mitochondrial protease caseinolytic protease P (ClpP). Downstream of target engagement, ONC201 activates the ATF4/CHOP-mediated integrated stress response leading to TRAIL/Death Receptor 5 (DR5) activation, inhibits oxidative phosphorylation via c-myc, and inactivates Akt/ERK signaling in tumor cells. This typically results in DR5/TRAIL-mediated apoptosis of tumor cells; however, DR5/TRAIL-independent apoptosis, cell cycle arrest, or antiproliferative effects also occur. The effects of ONC201 extend beyond bulk tumor cells to include cancer stem cells, cancer associated fibroblasts and immune cells within the tumor microenvironment that can contribute to its efficacy. ONC201 is orally administered, crosses the intact blood brain barrier, and is under evaluation in clinical trials in patients with advanced solid tumors and hematological malignancies. ONC201 has single agent clinical activity in tumor types that are enriched for DRD2 and/or ClpP expression including specific subtypes of high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors. Synergy with radiation, chemotherapy, targeted therapy and immune-checkpoint agents has been identified in preclinical models and is being evaluated in clinical trials. Structure-activity relationships based on the core pharmacophore of ONC201, termed the imipridone scaffold, revealed novel potent compounds that are being developed. Imipridones represent a novel approach to therapeutically target previously undruggable GPCRs, ClpP, and innate immune pathways in oncology.

A Novel Therapeutic Mechanism of Imipridones ONC201/ONC206 in MYCN-Amplified Neuroblastoma Cells via Differential Expression of Tumorigenic Proteins

“…In the TRAIL-dependent mechanism of action, ONC201 induces dual inactivation of AKT and ERK signaling pathways resulting in dephosphorylation of the transcription factor FOXO3a (Forkhead/winged-helix-box-class-O3), thus, leading to the upregulation of TRAIL expression (8). Moreover, ONC201 and its potent analog ONC206 were further reported to induce human mitochondrial caseinolytic protease P (ClpP) regulation and dopamine receptor DRD2 antagonism (13). On the other hand, in hematological tumors, ONC201 causes apoptotic effects by inducing prolonged integrated stress response (14) such stress response, the transcription factor ATF4 is activated and subsequent expression of pro-apoptotic genes such as CHOP is induced (15).…”

Reprogramming of the Caseinolytic Protease by ADEP Antibiotics: Molecular Mechanism, Cellular Consequences, Therapeutic Potential

“…Phase II clinical studies with positive outcomes were reported for refractory solid tumors ( Stein et al, 2017 ) and glioblastoma, indicating that ONC201 can pass the blood-brain barrier ( Arrillaga-Romany et al, 2017 ). ONC201 demonstrated substantial activity as a single agent and synergy in combination with other anticancer drugs ( Prabhu et al, 2020 ). Preclinical investigations demonstrated enhanced activity of newer analogs from the same class (e.g., ONC212, alternative name TR31; see Figure 4 ) and suggest broad applicability to diverse types of cancer ( Wagner et al, 2018 ; Aminzadeh-Gohari et al, 2020 ; Bonner et al, 2020 ; Jacques et al, 2020 ; Zhang et al, 2020 ).…”

Neuro-Signals from Gut Microbiota: Perspectives for Brain Glioma

“…In GBM, the dopamine receptor D2 (DRD2) is overexpressed in comparison with other dopamine receptors and the overexpression is associated with a poor prognosis [ 155 ]. In addition, DRD2 activation is responsible for the mitogenic signaling in GBM through the sequential activation of RAP1-GTP, Raf-1 release, and MEK/ERK signaling [ 156 ].A selective inhibitor of DRD2 (ONC201), now in clinical trial for different solid tumors and recurrent GBM (NCT02525692) [ 157 ], inhibits the cellular proliferation of cancer stem cell-enriched neurospheres obtained from primary and recurrent GBM, and induces apoptosis in stem cell-like glioma cells [ 158 , 159 ].…”