Based on the ideal drug-like characteristics of ONC201 (safety, pharmacokinetics (PK), pharmacodynamics (PD), solubility, chemical stability) and its novel pharmacophore, a medicinal chemistry effort was undertaken to define a structure-activity relationship (SAR) for this novel chemical scaffold. The SAR led to the identification of new imipridones that have increased potency, altered spectrums of activity in cancer, and differential engagement of distinct GPCR targets and ClpP in oncology. Minor chemical changes cause dramatic shifts in modality, selectivity and potency.
The imipridone scaffold provides therapeutic opportunities for many cancers and other diseases through selective modulation of GPCRs and ClpP and distinct downstream mechanisms.
The ability of imipridones to target GPCRs with a high degree of selectivity represents a novel opportunity in oncology that can generate remarkably safe and effective therapeutics. The chemistry behind this core structure permits the generation of a large imipridone family of compounds with vast therapeutic potential. Research shows that minor chemical changes cause dramatic shifts in: