Identification of NAE Inhibitors Exhibiting Potent Activity in Leukemia Cells: Exploring the Structural Determinants of NAE Specificity

• Published in: ACS medicinal chemistry letters Vol. 2; no. 8; pp. 577 - 582
• Main Authors: Lukkarila, Julie L., da Silva, Sara R., Ali, Mohsin, Shahani, Vijay M., Xu, G. Wei, Berman, Judd, Roughton, Andrew, Dhe-Paganon, Sirano, Schimmer, Aaron D., Gunning, Patrick T.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11.08.2011
• Subjects: Letter; leukemia; proteasomal inhibitors; anticancer drugs; NAE inhibitors
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml2000615

MLN4924 is a selective inhibitor of the NEDD8-activating enzyme (NAE) and has advanced into clinical trials for the treatment of both solid and hematological malignancies. In contrast, the structurally similar compound 1 (developed by Millennium: The Takeda Oncology Company) is a pan inhibitor of the E1 enzymes NAE, ubiquitin activating enzyme (UAE), and SUMO-activating enzyme (SAE) and is currently viewed as unsuitable for clinical use given its broad spectrum of E1 inhibition. Here, we sought to understand the determinants of NAE selectivity. A series of compound 1 analogues were synthesized through iterative functionalization of the purine C6 position and evaluated for NAE specificity. Optimal NAE specificity was achieved through substitution with primary N-alkyl groups, while bulky or secondary N-alkyl substituents were poorly tolerated. When assessed in vitro, inhibitors reduced the growth and viability of malignant K562 leukemia cells. Through this study, we have successfully identified a series of sub-10 nM NAE-specific inhibitors and thereby highlighted the functionalities that promote NAE selectivity.