Innovating Your Drug Discovery

Discovering a New Class of Anti-Cancer Compounds

Oncoceutics, Inc. is a clinical-stage biotech company developing a novel class of small molecule compounds for oncology called imipridones that selectively target G protein-coupled receptors (GPCRs).   Unique to all imipridones is a three-ring heterocyclic core structure. This structure provides imipridones with many ideal drug properties, including solubility and bioavailability, and is critical to their distinct mechanisms of action. Oncoceutics’ lead imipridone is ONC201, which was discovered using a phenotypic screen in 2009 and licensed to Oncoceutics in 2012. Following the discovery of the compound, Oncoceutics and its collaborators elucidated the mechanism that leads to ONC201’s anti-cancer effects that involve activation of the integrated stress response and inactivation of Ras signaling.  However, despite understanding the effects of ONC201 on these signaling pathways, the binding target that ONC201 utilized to impact those pathways was unknown.

3D structure of ONC201

3D Structure of ONC201: Clinical Stage Imipridone

Discovery of DRD2 as the Binding Target of ONC201

Working with DiscoverX, the road to discovering the binding target of ONC201 began with testing targets of FDA-approved oncology drugs, including kinases, proteases, and nuclear hormone receptors. ONC201 did not interact with any of these proteins.  Then, utilizing the DiscoverX PathHunter® platform, ONC201 was screened against a receptor panel comprising about 70% of all known human GPCRs. Though GPCRs are targeted by about 40% of prescription drugs, they have historically been underexploited in oncology despite the fact that GPCRs play important roles in cancer.  In particular, research suggests that GPCRs are hijacked by the majority of cancers, control an array of pro-survival signaling (e.g. Ras) and alleviate stress pathways (e.g. integrated stress response) in cancer cells. Additionally, GPCRs are attractive therapeutic targets because they are amenable to targeting in cancer cells without causing toxicity to normal cells.

Through the PathHunter screen, it was discovered that the compound selectively antagonizes the GPCR D2 dopamine receptor (DRD2). This unexpected finding was announced in a late breaking abstract at the 2016 AACR annual meeting. Further research validated that the DRD2 antagonism by ONC201 can be observed in human patients and that the interaction triggers ONC201’s impact on downstream signaling pathways and tumor cell death. The oncogenic role of DRD2 in cancer is increasingly appreciated in preclinical and clinical literature. A review summarizing this literature was written by Oncoceutics and recently published in Drug Discovery and Development.

Imipridones as a Platform to Selectively Target GPCRs

Since the initial discovery of the interaction between ONC201 and DRD2, Oncoceutics has begun screening additional imipridones utilizing DiscoverX’s GPCR platform. These studies have revealed that other imipridones, with the same core structure and minor modifications from ONC201, have the ability to target different GPCRs with a high degree of specificity. As a result, it is increasingly clear that the imipridone family contains members that bind to distinct targets, leading to distinct spectrums of activity, while maintaining ideal drug-like characteristics. Oncoceutics has already identified three lead imipridones that selectively engage GPCRs, impact known anti-cancer signaling pathways, and impart significant in vitro and in vivo efficacy in advanced cancer models. With issued patents covering more than a million potential compounds, the company continues to leverage DiscoverX’s platform and expertise to better understand and develop additional imipridones that exploit the therapeutic potential of the GPCR superfamily.

Article courtesy of Oncoceutics, Inc.

Written by:

  • Joshua Allen, VP of Research and Development
  • Bryce Istvan, Associate Finance and Business Development
  • Varun Prabhu, Associate Research Scientist
  • Lee Schalop, Chief Business Officer