Identification of NAE Inhibitors Exhibiting Potent Activity in Leukemia Cells: Exploring the Structural Determinants of NAE Specificity
- ACS Med Chem Lett. 2011 May 16;2(8):577-82. doi: 10.1021/ml2000615.
- 1. Department of Chemistry, University of Toronto Mississauga , 3359 Mississauga Road North, Mississauga, ON, L5L1C6, Canada.
- 2. Division of Hematology and Oncology, The Princess Margaret Hospital and the Ontario Cancer Institute , 610 University Avenue, Toronto, ON, M5G2M9, Canada.
- 3. Dalton Medicinal Chemistry Inc. , 349 Wildcat Road, Toronto, ON, M3J 2S3, Canada.
- 4. Structural Genomics Consortium, University of Toronto , 100 College Street, Toronto, ON, M5G1L5, Canada.
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.