Imipridones – A Novel Class of Anti-Cancer Molecules

Imipridones are a novel class of small molecule anti-cancer compounds that possess a unique three-ring heterocyclic core structure with two substitutable basic amines. The full chemical name for this novel core structure is 1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one. This structure imparts many ideal drug properties to imipridones and is critical to their distinct mechanisms of action.

Imipridones target specific G protein-coupled receptors (GPCRs) that control critical signaling pathways in cancer cells. The first imipridone to enter clinical development is ONC201, which directly antagonizes a GPCR called DRD2.  ONC206 and ONC212 are imipridones that have emerged as IND candidates based on potent and selective engagement of GPCR targets and tumor cell death.

All of Oncoceutics’ small molecule anti-cancer compounds are members of the imipridone class.

ONC201 (benzyl-benzylmethyl-imipridone)

ONC201 is the founding member of the imipridone class. The compound exhibits attractive drug-like chemical and physical characteristics: excellent chemical stability, high aqueous solubility at low pH, and high lipophilicity at physiological pH.  These attributes enable oral bioavailability that achieves therapeutic concentrations and wide distribution throughout the body to target tissues, including brain, bone marrow and lymph nodes. ONC201 has excellent activity in preclinical models of advanced cancers that no longer respond to standard-of-care treatments. The antitumor activity of ONC201 is linked to ONC201’s ability to target DRD2 with a high degree of selectivity and a rapid dissociation rate. Furthermore, decades of clinical experience with selective GPCR antagonists for indications outside of oncology have shown that drugs which target this superfamily are generally well tolerated, unlike most cancer therapies. Clinical trials have demonstrated clinical safety of ONC201 in trials along with a therapeutic pharmacokinetic (PK) profile, induction of pharmacodynamic (PD) markers, and early efficacy signals in a number of different types of cancer, including acute myeloid leukemia, non-Hodgkin’s lymphoma, prostate and endometrial cancers.

ONC206 (benzyl-flurobenzyl imipridone)

ONC206 is a benzyl-flurobenzyl imipridone that has highly potent activity in preclinical models of difficult-to-treat neuroendocrine tumors and sarcomas.

ONC212 (benzyl-alkylflurobenzyl imipridone)

ONC212 is a benzyl-alkylflurobenzyl imipridone that has potent activity in preclinical models of acute leukemias.