Combination of the First-in-Class Imipridone ONC201 and Standard Anticancer Therapies as a Rational Approach for Therapeutic Benefit

The development of drugs for cancer treatment faces critical challenges due to the heterogeneity in cancers, metastatic nature of the disease, lack of efficacy, toxicity, and drug resistance. This makes it quite important to understand the complexities of cancer as well as the limitations of druggable targets. ONC201 (also known as dordaviprone/TIC10/ModeysoTM), a first-in-class member of the imipridone family, has been shown to kill cancer cells selectively. Recently, it has received FDA approval as the first and only treatment for recurrent H3K27M-mutant diffuse midline glioma. The unique pharmacophore, favorable therapeutic index, ability to induce TRAIL and the integrated stress response (ISR), activation of natural killer cells, and ability to diffuse across the blood–brain barrier are the unique characteristics of ONC201. ONC201 has shown effectiveness against various cancers, and this has been evident in many preclinical studies. ONC201 as a single agent, although useful, has some limitations, which could be addressed by using combination strategies. ONC201 has shown synergism with other drugs, leading to greater tumor cell death or reduced tumor growth. Next-generation imipridones, viz. ONC206 and ONC212, are more potent analogs of ONC201 and exhibit similar characteristics. In this review, we discuss the therapeutic potential of ONC201 and its analogs using combination strategies across different cancers.