2. Academic Validation
  3. SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy

SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy

  • Neoplasia. 2022 Oct;32:100823. doi: 10.1016/j.neo.2022.100823.
Li-Na Zhou 1,  Chaodong Xiong 2,  Yong-Jun Cheng 3,  Shan-Shan Song 1,  Xu-Bin Bao 1,  Xia-Juan Huan 1,  Tong-Yan Wang 1,  Ao Zhang 4,  Ze-Hong Miao 5,  Jin-Xue He 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, China.
  • 2 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China; Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 4 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China; Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, China. Electronic address: ao6919zhang@sjtu.edu.cn.
  • 5 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, China. Electronic address: zhmiao@simm.ac.cn.
  • 6 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. Electronic address: jinxue_he@simm.ac.cn.
PMID: 35907292 DOI: 10.1016/j.neo.2022.100823
Abstract

Inhibition of the NEDD8-activating Enzyme (NAE), the key E1 Enzyme in the neddylation cascade, has been considered an attractive Anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC50 value of 0.36 nM and exhibited more than 2855-fold selectivity over the closely related Ubiquitin-activating Enzyme (UAE). It is worth noting that treatment with SOMCL-19-133 prominently inhibited Cullin neddylation and delayed the turnover of a panel of Cullin-RING ligases (CRLs) substrates (e.g., Cdt1, p21, p27, and Wee1) at lower effective concentrations than that of MLN4924, subsequently caused DNA damage and Chk1/Chk2 activation, and thus triggered cell cycle arrest and Apoptosis. Moreover, SOMCL-19-133 exhibited potent antiproliferative activity against a broad range of human tumor cell lines (mean IC50 201.11 nM), which was about 5.31-fold more potent than that of MLN4924. In vivo, oral delivery treatments with SOMCL-19-133, as well as the subcutaneous injection, led to significant tumor regression in mouse xenograft models. All of the treatments were well tolerated on a continuous daily dosing schedule. Compared with MLN4924, SOMCL-19-133 had a 5-fold higher peak plasma concentration, lower plasma clearance, and a 4-fold larger area under the curve (AUClast). In conclusion, SOMCL-19-133 is a promising preclinical candidate for treating cancers owing to its profound in vitro and in vivo efficacy and favorable pharmacokinetic properties.

Keywords

MLN4924; NAE inhibitor; NEDD8; Oral administration; SOMCL-19-133.

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