PT  - JOURNAL ARTICLE
AU  - Jessica N. Spradlin
AU  - Xirui Hu
AU  - Carl C. Ward
AU  - Scott M. Brittain
AU  - Lisha Ou
AU  - Dirksen E. Bussiere
AU  - Jason R. Thomas
AU  - John A. Tallarico
AU  - Jeffrey M. McKenna
AU  - Markus Schirle
AU  - Thomas J. Maimone
AU  - Daniel K. Nomura
TI  - Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation
AID  - 10.1101/436998
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 436998
4099  - http://biorxiv.org/content/early/2018/10/15/436998.short
4100  - http://biorxiv.org/content/early/2018/10/15/436998.full
AB  - Nimbolide, a terpenoid natural product derived from the Neem tree, impairs cancer pathogenicity across many types of human cancers; however, the direct targets and mechanisms by which nimbolide exerts its effects are poorly understood. Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. Nimbolide impairs breast cancer cell proliferation by disrupting RNF114 substrate recognition, leading to inhibition of ubiquitination and degradation of the tumor-suppressor p21, resulting in its rapid stabilization. We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Our study highlights the utility of ABPP platforms in uncovering unique druggable modalities accessed by natural products for cancer therapy and drug discovery applications.