The clinical success of bortezomib has demonstrated that targeting the Ubiquitin Proteasome System (UPS) can be a viable strategy to treat cancer. A second class of targets within the UPS are the E1 activating enzymes including UBA3 (NEDD8 Activating Enzyme) and UBA1 (Ubiquitin Activating Enzyme.) Millennium has pioneered the discovery of mechanism based small molecule E1 inhibitors that form covalent adducts with the Ubl substrates of E1s. MLN4924, a UBA3 inhibitor, is the first example of this class of inhibitors to enter clinical trials.  We have extended our efforts to UBA1, which regulates activation of ubiquitin.  We have identified potent inhibitors of UBA1 that, in cultured cells and mouse xenograft models, result in a significant reduction of ubiquitin conjugates and in the accumulation of UPS substrates. The inhibitors display strong antitumor activity in several xenograft models, suggesting that inhibition of UBA1 is a promising strategy to treat cancer.

Discovery of small molecule inhibitors of E1 activating enzymes

244th National Meeting (2012)

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