Abstract 349: Structure-activity relationships and mechanistic analysis of analogues of the clinical-stage anti-cancer small molecule ONC201
Authors: Wagner Jessica , Olson Gary , Bhaskara Nallaganchu Rao , Pottorf Richard S. , Mathew Garnett J. , Benes Cyril H. , Tarapore Rohinton , Stogniew Martin , Schalop Lee , Oster Wolfgang , Allen Josh E. , El-Deiry Wafik S. 
Published: July 2016

Abstract
TRAIL is an endogenous protein that initiates apoptosis selectively in cancer without toxic side effects, prompting interest in therapeutic modulation. We previously screened for small molecules that could upregulate the endogenous TRAIL gene to trigger apoptosis and restore anti-tumor immunity within tumor cells in a p53-independent manner. We showed that ONC201 (previously referred to as TIC10) is a dual inactivator of Akt and ERK, leading to nuclear translocation of Foxo3a and TRAIL gene activation (Allen et al., Science Translational Medicine, 2013). We recently found that ONC201 causes an early-stage upregulation of the integrated stress response through ATF4/CHOP/DR5 (Kline et al., Science Signaling, in press) and can inhibit cancer stem cell self-renewal (Prabhu et al., Cancer Research, 2015). ONC201 recently completed its first-in-man phase I clinical trial and several other trials in select advanced cancers are ongoing (NCT02250781, NCT02324621, NCT02420795, NCT02392572, NCT02609230, NCT02525692, NCT02038699). Leveraging the unique pharmacophore of ONC201, we synthesized ONC201 analogues in search for compounds with distinct therapeutic properties. After establishing the importance of the pyrido[3,4-e]pyrimidinone core structure of ONC201 in its anti-tumor activity (Wagner et al., Oncotarget, 2014), we performed detailed structure activity relationship (SAR) studies. We evaluated several ONC201 analogues with differing N-substituents around the core structure. Certain ONC201 analogues exhibit more rapid kinetics of activity and lowered IC50 values in some human cancer cell lines in vitro. Interim results of ONC212 sensitivity profiling in &gt;100 genetically annotated cell lines from the Genomic of Drug Sensitivity in Cancer collection have corroborated this improvement in potency. One analogue, ONC212, has demonstrated compelling efficacy against several tumor types in vivo with no evidence of toxicity at therapeutic doses. Furthermore, in vitro mechanism studies have demonstrated overlap between ONC201- and ONC212-mediated signaling in tumor cells that includes activation of the integrated stress response. With a wide safety margin, distinct pharmacokinetics (PK), and robust potency, ONC212 is being developed as the next drug candidate from the new class of compounds defined by the novel pharmacophore of ONC201 in indications that complement the parent compound's use spectrum.
Citation Format: Jessica Wagner, Gary Olson, Nallaganchu Rao Bhaskara, Richard S. Pottorf, Garnett J. Mathew, Cyril H. Benes, Rohinton Tarapore, Martin Stogniew, Lee Schalop, Wolfgang Oster, Josh E. Allen, Wafik S. El-Deiry. Structure-activity relationships and mechanistic analysis of analogues of the clinical-stage anti-cancer small molecule ONC201. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 349.