Improved nonclinical safety profile of a novel, highly selective inhibitor of the immunoproteasome subunit LMP7 (M3258).

Abstract

M3258 is the first selective inhibitor of the immunoproteasome subunit LMP7 (Large multifunctional protease 7) in early clinical development with the potential to improve therapeutic utility in patients of multiple myeloma (MM) or other hematological malignancies. Safety pharmacology studies with M3258 did not reveal any functional impairments of the cardiovascular system in several in vitro tests employing human cardiomyocytes and cardiac ion channels (including hERG), guinea pig heart refractory period and force contraction, and rat aortic contraction as well as in cardiovascular function tests in dogs. Following single dose M3258 administration to rats, no changes were observed on respiratory function by using whole body plethysmography, nor did it change (neuro)behavioral parameters in a battery of tests. Based on pivotal 4-week toxicity studies with daily oral dosing of M3258, the identified key target organs of toxicity were limited to the lympho-hematopoietic system in rats and dogs, and to the intestine with its local lymphoid tissues in dogs only. Importantly, the stomach, nervous system, heart, lungs, and kidneys, that may be part of clinically relevant toxicities as reported for pan-proteasome inhibitors, were spared with M3258. Therefore, it is anticipated that by targeting highly selective and potent inhibition of LMP7, the resulting favorable safety profile of M3258 together with the maintained potent anti-tumor activity as previously reported in mouse MM xenograft models, may translate into an improved benefit-risk profile in MM patients.

• Authors: Willem Sloot, Nina Glaser, Annika Hansen, Juergen Hellmann, Sven Jaeckel, Sigrid Johannes, Anja Knippel, Valentina Lai, Manuela Onidi
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 429 Pg. 115695 (10 15 2021) ISSN: 1096-0333 [Electronic] United States
• PMID: 34419493 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Boronic Acids
• Furans
• M3258
• Proteasome Inhibitors
• LMP7 protein
• Proteasome Endopeptidase Complex

Topics

• Administration, Oral
• Animals
• Boronic Acids (administration & dosage, toxicity)
• Cells, Cultured
• Dogs
• Female
• Furans (administration & dosage, toxicity)
• Guinea Pigs
• Hematopoietic System (drug effects, pathology)
• Humans
• Intestines (drug effects, pathology)
• Lymphatic System (drug effects, pathology)
• Male
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors (administration & dosage, toxicity)
• Rats, Wistar
• Risk Assessment
• Species Specificity
• Toxicity Tests
• Rats