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Lukkarila J.L.,University of Toronto | Da Silva S.R.,University of Toronto | Ali M.,Ontario Cancer Institute | Shahani V.M.,University of Toronto | And 6 more authors.
ACS Medicinal Chemistry Letters | Year: 2011

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. © 2011 American Chemical Society.

Cote J.B.,Dalton Medicinal Chemistry Inc. | Cote J.B.,Hunter Group Ltd | Roughton A.,Dalton Medicinal Chemistry Inc. | Nasielski J.,Dalton Medicinal Chemistry Inc. | And 3 more authors.
Tetrahedron Letters | Year: 2011

The acid mediated cyclization of a protected N-acylhydroxyguanidine into the corresponding 3-amino-1,2,4-oxadiazole and confirmation of its structure by single crystal X-ray crystallography is reported herein. The yield of the cyclization is comparable to literature reports utilizing alternative procedures. Importantly, these new conditions provide complementary chemoselectivity to current synthetic procedures which may be useful for the synthesis of 3-amino-1,2,4-oxadiazoles in general. © 2011 Elsevier Ltd. All rights reserved.

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