Evaluation of the Proteasome Inhibitor MLN9708 in Preclinical Models of Human Cancer

TLDR

The proteasome has emerged as a validated oncology target following the clinical success of VELCADE for multiple myeloma and mantle cell lymphoma, prompting development of additional small‑molecule inhibitors for hematologic and solid tumors. This study introduces MLN9708, a selective, orally bioavailable second‑generation proteasome inhibitor currently in phase I clinical development. MLN9708 is engineered to inhibit the proteasome with a shorter dissociation half‑life and improved pharmacokinetics compared to bortezomib. MLN9708 shows a shorter proteasome dissociation half‑life, enhanced pharmacokinetics and pharmacodynamics, greater tissue‑level proteasome inhibition, and potent antitumor activity in both solid and hematologic xenograft models, supporting its clinical development.

Abstract

The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, several groups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications.