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
Department of Chemistry, University of Toronto Mississauga , 3359 Mississauga Road North, Mississauga, ON, L5L1C6, Canada.
Division of Hematology and Oncology, The Princess Margaret Hospital and the Ontario Cancer Institute , 610 University Avenue, Toronto, ON, M5G2M9, Canada.
ACS Med Chem Lett. 2011 May 16;2(8):577-82. doi: 10.1021/ml2000615. eCollection 2011 Aug 11.
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.
MLN4924是NEDD8激活酶（NAE）的选择性抑制剂，已进入治疗实体瘤和血液系统恶性肿瘤的临床试验阶段。相比之下，结构相似的化合物1（由千禧公司：武田肿瘤公司研发）是E1酶NAE、泛素激活酶（UAE）和SUMO激活酶（SAE）的泛抑制剂，鉴于其对E1的广泛抑制作用，目前被认为不适合临床使用。在此，我们试图了解NAE选择性的决定因素。通过嘌呤C6位的迭代功能化合成了一系列化合物1类似物，并评估了它们的NAE特异性。通过用伯N-烷基取代可实现最佳的NAE特异性，而大体积或仲N-烷基取代基的耐受性较差。在体外评估时，抑制剂降低了恶性K562白血病细胞的生长和活力。通过这项研究，我们成功鉴定出一系列纳摩尔浓度以下的NAE特异性抑制剂，从而突出了促进NAE选择性的功能基团。
