Abstract
Introduction: More than 70% of multiple myeloma (MM) cases occur in elderly patients over the age of 65 years, and the incidence of MM has remarkably increased in Korea over the past 20 years; thus, it is necessary to discover a new therapeutic agent that can be safely used in elderly patients. Lenalidomide-based therapeutics and proteasome inhibitors, which are currently used as the basis for the treatment of MM in clinical practice, have accompanying systemic side effects, such as pancytopenia, peripheral neuropathy, and severe skin lesions. Therefore, it is necessary to develop new therapeutic agents that can overcome the serious side effects, treatment tolerance, or resistance to these therapeutic agents.
Methods: A chromanone-based (KBB-NX derivatives) low-molecular weight compound was synthesized by targeting prohibitin (PHB), which is our own companion diagnostic marker for hematologic cancers, such as MM. For the synthesized low-molecular weight synthetic substances, candidate synthetic compounds were identified through efficacy verification tests at the cell line level, blood stability tests, pharmacokinetic tests using laboratory animals, and single-dose toxicity tests. Further, after conducting an efficacy test using the mouse MM model that we built ourselves, we performed a study to discover a lead compound that can be used for non-clinical testing at the Good Laboratory Practices level.
Results: In this study, 30 types of KBB-NX-based active substances that had an apoptotic effect on MM cells by blocking the PHB2 protein were obtained. When MM cells were treated with these active substances, the PHB2 function was inactivated to increase the intracellular reactive oxygen species (ROS) production, and then, proapoptotic and anti-proliferative effects were induced to kill MM cells. Among the discovered active substances, when a MM cell line was exposed to KBB-NX16, the amount of the target PHB2 protein was decreased by more than 90%, confirming the high molecular-target binding ability. Among the compounds synthesized by itself as a KBB-NX derivative, KBB-NX20 was found to have an IC50 of less than 1 μM. In the initial pharmacokinetic test for KBB-NX16 and KBB-NX20 compounds, which was conducted using rats, their half-lives were very short, less than 1 hour and 40 minutes; hence, there was a need for formulation studies. The need for early pharmacokinetic testing was increased.
Conclusions: We identified effective substances from PHB-targeted chromanone compounds for the treatment of MM using an apoptosis mechanism through excessive production of intracellular ROS. These results suggested derivatives of PHB2 target chromanone compounds as candidates for MM-targeted anticancer drugs.
Keywords: Multiple myeloma, PHB2, Targeted anticancer drugs, Chromanone compound
Disclosures
No relevant conflicts of interest to declare.
