Abstract LB-209: D2-like dopamine receptor antagonism by ONC201 identified by confluence of computational, receptor binding, and clinical studies

Abstract

Abstract ONC201 is a first-in-class small molecule discovered in a phenotypic screen for p53-independent inducers of tumor-selective pro-apoptotic pathways. Oral ONC201 is currently being evaluated at leading institutions as a new therapeutic agent in five early phase clinical trials for select advanced cancers based on pronounced efficacy in aggressive and refractory tumors and excellent safety. Here, we report the prediction and validation of selective direct molecular interactions between ONC201 and specific members of the dopamine receptor family. One initial prediction of this interaction was derived from the BANDIT drug target prediction method. BANDIT combines millions of data points from clinical, genomic, chemical and structural datasets within a Bayesian network to predict the targets of small molecules. The molecular structure of ONC201, its in vitro efficacy profile, and its publicly available bioactivity assay results were used as inputs for BANDIT and ONC201 was tested against all small molecules with known targets. Results of the BANDIT analysis indicated that ONC201 was highly correlated with other small molecules known to target DRD2, a member of the dopamine receptor family of GPCRs. Furthermore, BANDIT predicted a highly specific binding to DRD2 rather than other members of the dopamine receptor family. In parallel to these independent in silico predictions, experimental GPCR profiling indicated that ONC201 selectively antagonizes the D2-like, but not D1-like, subfamily of dopamine receptors. Reporter assays in a heterologous expression system revealed that ONC201 selectively antagonizes both short and long isoforms of DRD2 and DRD3, with weaker potency for DRD4 and no antagonism of DRD1 or DRD5. Increased secretion of prolactin is a clinical hallmark of DRD2 antagonism by several psychiatric medications that potently target this receptor. ELISA measurements in the peripheral blood of patients who were treated with ONC201 in the first-in-human trial with advanced solid tumors determined that 10/11 patients evaluated in this analysis exhibited induction of prolactin (mean of 2-fold). Using the TCGA database, we found that the D2-like subfamily of dopamine receptors, particularly DRD2, is prevalent and selectively overexpressed in several malignancies. Preclinical reports show that DRD2 inhibition imparts antitumor efficacy, without killing normal cells, via induction of ATF4/CHOP and inhibition of Akt and ERK signaling that are all attributes of ONC201. In summary, antagonizing the D2-like family of dopamine receptors appears to be a promising therapeutic target in oncology, and ONC201 is the first compound to exploit this treatment paradigm in several ongoing Phase II clinical studies. Citation Format: Neel S. Madhukar, Olivier Elemento, Cyril H. Benes, Mathew J. Garnett, Mark Stein, Joseph R. Bertino, Howard L. Kaufman, Isabel Arrillaga-Romany, Tracy T. Batchelor, Lee Schalop, Wolfgang Oster, Martin Stogniew, Michael Andreeff, Wafik S. El-Deiry, Joshua E. Allen. D2-like dopamine receptor antagonism by ONC201 identified by confluence of computational, receptor binding, and clinical studies. [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 LB-209.