NHR2 inhibitors - Treatment of AML by inhibitors of NHR2 and/or RUNX1/ETO-tetramerization


Ref.-Nr. 3409

The formation and onset of the prevalent form of acute myeloid leukemia (AML, FAB subtype M2) requires RUNX1/ETO, the product of the t(8;21) chromosomal translocation. Tetramerization through the nervy homology region 2 (NHR2) of ETO is essential for the RUNX1/ETO-mediated transformation. The inventors demonstrated that inhibition of NHR2 tetramerization by first-in-class small molecules is a viable entry point for the treatment of AML.

Drug candidates have been identified by a small-molecule in silico screening and have been validated in cellular assays. Several compounds proved to be successful in inhibiting NHR2 tetramerization.

Preferred compound 7.44 was able to slow tumor growth in a xenograft mouse model (SKNO 1 xenograft).

The pending patent application covers claims directed to a variety of chemotypes that proved activity against AML.

Commercial Opportunities

On behalf of University of Düsseldorf, PROvendis offers this opportunity for licensing or co-development.

Current Status

A PCT application has been filed; WO2014177464 A2.

Relevant Publications

Wichmann et al.: Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity, Blood 2010, 116(4), 603-613.
Metz et al.: From Determinants of RUNX1/ETO Tetramerization to Small-Molecule Protein-Protein Interaction Inhibitors Targeting Acute Myeloid Leukemia, J. Chem. Inf. Model. 2013, 53(9), 2197-202.
Schanda et al.: Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of NHR2 tetramerization, manuscript available upon request.

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