Discovery and clinical introduction of first-in-class imipridone ONC201

Abstract

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

Keywords: ATF4; DRD2; ONC201; TIC10; integrated stress response.

Figure 1. Molecular Structure of ONC201

Figure 2. Mechanism of action of ONC201

Figure 3. In vitro sensitivity of human cancer cell lines to ONC201

In vitro sensitivity of 1000 human cancer cell lines to ONC201 averaged and organized by tumor type. The results are shown as completeness of ONC201 response quantified as the area under the curve (AUC) in the dose-response cell viability curve averaged for all cell lines in each tumor type. Numbers above the bar indicate the number of cell lines tested per tumor type.

Figure 4. The pro-apopototic activity of ONC201 is sustained

TUNEL assay on HCT116 subcutaneous xenografts harvested following a single dose of ONC201 (25 mg/kg) at the indicated time points.

Figure 5. Proposed model for PK/PD-guided administration of ONC201 as a combinatorial anti-cancer agent

ONC201 is particularly attractive for combinatorial regimens due to a short half-life and PD that persists for days to weeks. Due to this unique PK/PD relationship, ONC201 could be administered one to two days prior to another anti-cancer agent that would allow for a synergistic PD overlap (green lines) while avoiding drug-drug interactions.

Figure 6. ONC201 synergizes with Bcl-2 inhibitors

Bcl-2 overexpression reduces ONC201-mediated cell death while high Mcl-1 levels are linked to ABT-199/ABT-263 resistance. The combined inhibition of Bcl-2 with ABT-263/ABT-199 and Mcl-1 with ONC201 (via Bag3/Usp9X inhibition) results in synergistic anti-tumor effects via the mitochondrial pathway of apoptosis involving Bax/Bak oligomerization, caspase activation and PARP-cleavage. Improved inhibition of Akt/ERK also contributes to the synergistic effects.