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.

Fig. 1

DRD2 Overexpression in Human Cancer. The indicated publications for each tumor type were identified through a PubMed search as of July 2020, as well as recent reviews of DRD2 in oncology , .

Fig. 2

ONC201 mechanism of action. (A) ONC201 affects bulk tumor cells, tumor stem cells and normal cells in the tumor microenvironment, including immune cells and fibroblasts, to elicit anti-cancer effects. DRD2 antagonism and ClpP activation by ONC201 are upstream events while downstream events include integrated stress response activation, c-myc downregulation, decreased OXPHOS, Akt/ERK inactivation, and Foxo3a activation that ultimately trigger DR5/TRAIL-mediated apoptosis. (B) ONC201 activates and increases intra-tumoral presence of NK, CD4+ and CD8+ T cells. Through an increase in IFN2α, IL-12p70 and IP-10, NK cells increase granzyme and TRAIL secretion, leading to tumor cell death .

Fig. 3

Single agent ONC201 efficacy in preclinical models of solid tumors and hematological malignancies. Publications that report the single-agent efficacy of ONC201 published as of July 2020. DSRCT: desmoplastic small round cell tumor. CRC: colorectal cancer

Fig. 4

Candidate predictive biomarkers for ONC201 by tumor location. DRD2/5: glioma; ClpP: AML, breast cancer; c-Myc: glioma; EGFR: glioma. Green: increased expression associated with increased tumor sensitivity to ONC201. Red: decreased expression associated with increased tumor sensitivity to ONC201.