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.
Highlights
ONC201 is a small molecule, chemical compound referred to as 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9hexahydroimidazo [1,2-a]pyrido [3,4-e]pyrimidin5(1H)-one that is the founding member of the imipridone class of compounds that share a unique heterocyclic pharmacophore (Figure 1)
Referred to as TNF-related apoptosis-inducing ligand (TRAIL)-inducing compound 10 (TIC10) based on the phenotype underpinning its discovery as an anti-tumor agent, ONC201 was selected as the lead compound for clinical development due to its favorable therapeutic index, lack of genotoxicity, druglike chemical properties, penetration of the blood-brain barrier, p53-independent efficacy in a panel of refractory solid tumor cell lines, and single-dose anti-tumor activity in vivo [1, 2]
This same gene signature was upregulated in Jeko-1 human mantle cell lymphoma cells in a time-dependent manner in response to ONC201 as early as 12 hours post-treatment
Summary
ONC201 is a small molecule, chemical compound referred to as 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9hexahydroimidazo [1,2-a]pyrido [3,4-e]pyrimidin5(1H)-one that is the founding member of the imipridone class of compounds that share a unique heterocyclic pharmacophore (Figure 1). ONC201 showed high selectivity of induction of cell death in malignant cells, unlike breflate that was toxic to normal cells [2] This early observation suggested a partial, but not complete overlap, in mechanism of action between ONC201 and ER stress-inducing compounds that would be elucidated subsequently. An in silico analysis of overlap between transcription factors with binding sites within the TRAIL gene promoter and potential transcriptional regulators of the mRNA changes observed in the GEP studies was performed This crossreferencing suggested that Foxo3a, which possesses a binding site within the TRAIL gene promoter [4], could be activated in response to ONC201. Chromatin-immunoprecipitation assays verified a dose-dependent increase in the amount of Foxo3a bound to the TRAIL gene promoter in response to ONC201 Both ONC201-induced TRAIL and overall anti-tumor efficacy was partially dependent on Foxo3a, as shown by RNA interference experiments in CRC models [1]
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