Abstract DDT02-01: First-time disclosure of M3258: A selective inhibitor of the immunoproteasome subunit LMP7 with potential for improved therapeutic utility in multiple myeloma compared to pan-proteasome inhibitors

Abstract

Large multifunctional peptidase 7 (LMP7, β5i, PSMB8) is a chymotrypsin-like proteolytic subunit of the immunoproteasome, which degrades ubiquitinated proteins and generates peptides for presentation on MHC class I. In contrast to the constitutive proteasome, which is broadly expressed, the immunoproteasome is specifically present in normal and malignant hematopoietic cells and can be induced in non-hematopoietic cells by inflammatory stimuli such as IFNγ. Pan-proteasome inhibitors like Bortezomib, which is approved in multiple myeloma and mantle cell lymphoma, indiscriminately inhibit the proteolytic activities of multiple subunits of the constitutive proteasome and immunoproteasome, including LMP7. Widespread proteasome inhibition is believed to underpin the adverse safety profiles of these agents and limit their therapeutic potential. Selective LMP7 targeting could achieve improved antitumor activity as a result of enhanced target inhibition, meanwhile circumventing the dose-limiting severe toxicities associated with pan-proteasome inhibitors. Based on the aforementioned hypothesis, a drug discovery program was initiated to identify selective inhibitors of LMP7. This led to the discovery of M3258, a covalent-reversible, potent, selective and orally-bioavailable inhibitor of LMP7. M3258 demonstrated strong in vivo antitumor activity, up to complete regression, in multiple myeloma xenograft models at daily oral doses as low as 1 mg/kg. This was associated with significant and prolonged suppression of tumor LMP7 activity. Furthermore, M3258 was efficacious in several multiple myeloma models that were refractory to Bortezomib. Subacute GLP toxicology studies with M3258, applied orally on a once-daily schedule, identified the lymphatic and hematopoietic systems in rat and dog and intestinal system in dog alone as main target organs. Importantly, M3258 was without effect on the peripheral and central nervous systems and cardiac and respiratory organs. Overall, M3258 demonstrated a superior preclinical therapeutic window and more restricted spectrum of toxicities compared to pan-proteasome inhibitors. Supported by robust preclinical data, clinical phase I assessment of M3258 in multiple myeloma patients is planned to begin in 2019. Citation Format: Michael Sanderson, Michael Busch, Christina Esdar, Manja Friese-Hamim, Mireille Krier, Jianguo Ma, Djordje Musil, Felix Rohdich, Willem Sloot, Gina Walter, Ugo Zanelli, Oliver Schadt, Markus Klein. First-time disclosure of M3258: A selective inhibitor of the immunoproteasome subunit LMP7 with potential for improved therapeutic utility in multiple myeloma compared to pan-proteasome inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr DDT02-01.

Design and Evaluation of Highly Selective Human Immunoproteasome Inhibitors Reveal a Compensatory Process That Preserves Immune Cell Viability

“…For example, acrylamide boronic acid 4 has improved selectivity for β5i; however, concerns exist that irreversible covalent inhibitors may obscure proteasome selectivity benefits especially in a nononcology patient population. Accordingly, we have focused on developing reversible inhibitors that specifically targeted the β5i subunit alone and in combination with the β1i subunit of the immunoproteasome …”

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

“…It is in clinical testing to treat autoimmune diseases [141], expanding the indications of proteasome inhibitors beyond cancer. Notably, a second immunoproteasome inhibitor, M3258, targeting β5i was disclosed and will be tested in combination with dexamethasone in an upcoming phase I clinical trial for treating MM [145].…”

Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein

“…More frequent dosing should lead to longer suppression of activity and reduce the likelihood of recovery of activity. M3258, a novel highly specific inhibitor of LMP7 may satisfy these requirements because it is dosed daily and is capable of continuous suppression of activity in mice 45 . It is undergoing clinical trials for the treatment of multiple myeloma.…”