Ubiquitin choke point

Takeda has shown its first-in-class UBA1 inhibitor could safely treat cancer by blocking a protein on which virtually all cells depend for ubiquitin-mediated protein degradation, upending conventional wisdom about how to disrupt the pathway that has focused drug developers on targets further downstream.

Three families of enzymes regulate the ubiquitination process that marks proteins for degradation: E1 ubiquitin-activating enzymes (UAEs), E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases. The E1 enzymes load ubiquitin onto the E2 enzymes, which then carry their cargo to specific proteins as directed by an E3 ubiquitin ligase...