. 2017 Sep 18;37(2):148–159. doi: 10.1038/onc.2017.313

Table 2. Approaches to target E3 ubiquitin ligase activity in CRC.

Compound	Class	Target	Proposed working mechanism	Refs
R-spondin	Protein/peptide	RNF43/ZNRF3	Neutralizes receptors and upregulates Wnt signaling	⁴¹
C59	porcupine inhibitor	Mutant RNF43/ZNRF3	Blocks Wnt niche function	^{131, 132}
LGK974	Small molecule Porcupine inhibitor	RNF43/ZNRF3	Prevents palmitylation of Wnt proteins and inhibits Wnt signaling	^{131, 132}
HLI98	Small molecule	MDM2	Inhibits MDM2 ubiquitin, activates p53 pathway and induces apoptosis	¹⁴¹
MX69	Small molecule	MDM2/XIAP	Degrades MDM2, activates p53 and inhibits XIAP	¹⁴²
Ceramide/LCL85	Small molecule	cIAP1/XIAP	Induces proteasomal degradation of cIAP1 and XIAP	¹⁴³
MLN4924	Small molecule	SCF E3 ubiquitin ligases	Induces G2/M arrest, apoptosis and DNA damage; inhibition of cullin neddylation	^{146, 147}
CC0651	Small molecule	E2 enzyme hCdc34 and SCF subunits Skp1, Cul1 and Rbx1	Causes the SCF^Skp2 substrate p27^Kip1 accumulation	^{149, 150}
Pro-TAME	Small molecule	APC/Cdc20	Disruption of the APC/Cdc20 interaction leading to lower APC/C activity on substrates	^{151, 152, 153}

Abbreviations: APC/C, anaphase-promoting complex/cyclosome; CRC, colorectal cancer; SCF, S phase kinase-associated protein 1–cullin1–F-box protein; XIAP, X-chromosome-linked apoptotic protein.