title: Identification of NAE Inhibitors Exhibiting Potent Activity in Leukemia Cells: Exploring the Structural Determinants of NAE Specificity.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , 3359 Mississauga Road North, Mississauga, ON, L5L1C6, Canada.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Lukkarila
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , 3359 Mississauga Road North, Mississauga, ON, L5L1C6, Canada.
authors.forename: Sara R
authors.initials: SR
authors.lastname: da Silva
authors.affiliation: Division of Hematology and Oncology, The Princess Margaret Hospital and the Ontario Cancer Institute , 610 University Avenue, Toronto, ON, M5G2M9, Canada.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Ali
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , 3359 Mississauga Road North, Mississauga, ON, L5L1C6, Canada.
authors.forename: Vijay M
authors.initials: VM
authors.lastname: Shahani
authors.affiliation: Division of Hematology and Oncology, The Princess Margaret Hospital and the Ontario Cancer Institute , 610 University Avenue, Toronto, ON, M5G2M9, Canada.
authors.forename: G Wei
authors.initials: GW
authors.lastname: Xu
authors.affiliation: Dalton Medicinal Chemistry Inc. , 349 Wildcat Road, Toronto, ON, M3J 2S3, Canada.
authors.forename: Judd
authors.initials: J
authors.lastname: Berman
authors.affiliation: Dalton Medicinal Chemistry Inc. , 349 Wildcat Road, Toronto, ON, M3J 2S3, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Roughton
authors.affiliation: Structural Genomics Consortium, University of Toronto , 100 College Street, Toronto, ON, M5G1L5, Canada.
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
authors.affiliation: Division of Hematology and Oncology, The Princess Margaret Hospital and the Ontario Cancer Institute , 610 University Avenue, Toronto, ON, M5G2M9, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , 3359 Mississauga Road North, Mississauga, ON, L5L1C6, Canada.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
keywords: NAE inhibitors; anticancer drugs; leukemia; proteasomal inhibitors