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KDM5 Selective Inhibitors for the Treatment of Multiple Myeloma and Other KDM-dependent Diseases
Dana-Farber
Small molecule
Oncology
Pre-Clinical
Multiple myeloma (MM), a type of cancer caused by disorders in the plasma cell, accounts for 10% of all hematologic malignancies. Over the years, considerable therapeutic progress has been made improving both the life expectancy and quality of life. Despite advances in targeted chemotherapy, MM remains incurable. Recent studies provided new pathophysiological insights in the role of epigenetic proteins including histone lysine demethylases (KDM’s). This family of enzymes regulate post-translation modifications in histones. Inhibition of KDMs has demonstrated antitumor effects.
One of these KDMs is lysine demethylase 5A (KDM5) which comprises a Jumonji C domain that removes histone H3 lysine 4 di- and trimethylation marks. KDM5 is involved in the development, differentiation, tumorigenesis, metastasis, and drug resistance in various cancers. The relevance of KDM5 in cell cycle control in diseases including MM and other cancers makes it a promising target for the development of therapeutics that modulate its activity.
Dana-Farber scientists have developed a series of novel compounds that inhibit KDM5’s enzymatic activity with greater potency compared to reported KDM5 inhibitors. Importantly, the new KDM5 inhibitors have a proven selectivity for the KDM5 family over other KDM subfamilies. Both in vitro and in vivo findings reveal the promise of these inhibitors as novel therapeutic strategies in MM and other KDM5A-dependent malignancies.
The series of new KDM5 inhibitors offers the following advantages:
The technology described offers a new research tool to study the role of KDM5; while the proven selectivity and early efficacy in vivo data show great promise for these KDM5 inhibitors as a new therapeutic strategy for MM and related cancers, and cardiovascular disease.
Qi Jun and Park Paul M.
PCT-US2019-045259 (2019.08.06)
Patent Family: PCT, EP, JP, CA, AU
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