Sure analyses revealed that K-7174 interacts with subunits largely via hydrophobic interaction, whereas bortezomib binds to the subunit via a hydrogen-bond network, explaining why higher concentrations are required for HPDs compared with bortezomib. Therefore, the development of novel HPDs with higher activity and specificity is essential for clinical translation. Our finding on the chemical structure of homopiperazine-derived PIs may be of great help in this regard. Despite the great success of bortezomib in the treatment of refractory malignancies such as MM and mantle cell lymphoma, we still intend to develop orally bioavailable PIs with distinct mechanisms of action from bortezomib. Several novel PIs, such as carfilzomib, NPI-0052, CEP-18770, MLN9708, and ONX-0912, are now undergoing clinical XG-102 chemical information trials and show considerable benefits for refractory/relapsed cases as well as untreated MM patients. Among them, carfilzomib and its derivative ONX-0912 are peptide derivatives and have greater selectivity for the ?5 subunit than bortezomib. Although NPI-0052 is a non-peptide PI targeting all three proteasome subunits, its effect was strong for chymotrypsin-like, moderate for 245342-14-7 trypsinlike, and weak for caspase-like activities. In addition, NPI-0052 is intravenously administered in clinical studies, although it is expected to have oral bioactivity. MLN9708 is orally available and its efficacy has been demonstrated in phase I clinical trials with oral administration ; however, this drug is speculated to be ineffective for MM carrying ?5-subunit mutations because of its boronate-based structure similar to bortezomib. Recently, in contrast to our speculation, Chauhan et al. reported the effectiveness of MLN9708 to overcome bortezomib resistance. As several mechanisms have been proposed for bortezomib resistance in addition to ?5 subunit mutations, MLN9708 may be effective for such cases. HPDs are expected to compensate for the weak points of bortezomib as well as the second generation PIs described above, because HPDs are non-peptide agents that inhibit all three catalytic subunits of the proteasome with equal kinetics and could be orally bioactive. Moreover, crystal structure analyses indicate that the binding mode is completely different from that of bortezomib and