Development of Potent NEDD8-Activating Enzyme Inhibitors Bearing a Pyrimidotriazole Scaffold
Chaodong Xiong1,2,3, Lina Zhou1,3, Jing Tan1,2,3
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
Abstract:
The ubiquitin-like protein NEDD8 is a critical signaling molecule implicated in the functional maintenance and homeostasis of cells. Dysregulation of this process is involved in a variety of human diseases, including cancer. Therefore, NEDD8-activating enzyme E1 (NAE), the only activation enzyme of the neddylation pathway, has been an emergent anticancer target. In view of the single-agent modest response of the clinical NAE inhibitor, pevonedistat (compound 1, MLN4924), efforts on development of new inhibitors with both high potency and better safety profiles are urgently needed. Here, we report a structural hopping strategy by optimizing the central deazapurine framework and the solvent interaction region of compound 1, leading to compound 26 bearing a pyrimidotriazole scaffold. Compound 26 not only has compatible potency in the biochemical and cell assays but also possesses improved pharmacokinetic (PK) properties than compound 1. In vivo, compound 26 showed significant antitumor efficacy and good safety in xenograft models.
Insights
Researchers developed a new anticancer drug candidate, compound 26, targeting NEDD8-activating enzyme E1 (NAE). This novel inhibitor shows improved properties over existing treatments and demonstrates significant antitumor efficacy with good safety in preclinical models.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The ubiquitin-like protein NEDD8 is crucial for cellular homeostasis.
- Dysregulation of NEDD8 pathways is linked to various diseases, notably cancer.
- NEDD8-activating enzyme E1 (NAE) is a key target for anticancer therapies.
Purpose of the Study:
- To develop novel NAE inhibitors with enhanced potency and safety profiles.
- To address the limitations of existing NAE inhibitors like pevonedistat (compound 1).
- To identify new anticancer drug candidates targeting the neddylation pathway.
Main Methods:
- Employed a structural hopping strategy to optimize compound 1.
- Modified the deazapurine framework and solvent interaction region.
- Synthesized and evaluated compound 26 with a pyrimidotriazole scaffold.
Main Results:
- Compound 26 demonstrated comparable potency to compound 1 in biochemical and cellular assays.
- Compound 26 exhibited improved pharmacokinetic properties compared to compound 1.
- In vivo studies showed significant antitumor efficacy and favorable safety of compound 26 in xenograft models.
Conclusions:
- Compound 26 represents a promising next-generation NAE inhibitor.
- The pyrimidotriazole scaffold offers a viable alternative for NAE inhibitor development.
- Further investigation of compound 26 is warranted for its potential as an anticancer therapeutic.
