Background:

MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme (NAE) with IC50 value of 4nM [1].

MLN4924 binds NAE within the nucleotide-binding site competing with AMP. It is a potent inhibitor of NAE and is selective relative to the closely related enzymes UAE, SAE, UBA6 and ATG7 with IC50 values of 1.5, 8.2, 1.8 and 10μM, respectively. MLN4924 shows no effect to other ATP-using enzymes. In HCT-116 cells, MLN4924 treatment results in a decrease of Ubc12–NEDD8 thioester and NEDD8–cullin conjugates, thus resulting in an inhibition of protein degradation mediated by CRL-ubiquitinylation. CDT1 is one of these proteins. The accumulation of CDT1 can cause cell-cycle defects. In mice bearing HCT-116 xenografts, administrations of MLN4924 at 30mg/kg and 60mg/kg significantly inhibit the tumor growth and these doses are well tolerated. The anti-tumour activity of MLN4924 is also found both in mice bearing H522 lung tumour xenografts and in mice bearing Calu-6 lung carcinoma xenografts [1].

参考文献:
[1] Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S, Cullis CA, Doucette A, Garnsey JJ, Gaulin JL, Gershman RE, Lublinsky AR, McDonald A, Mizutani H, Narayanan U, Olhava EJ, Peluso S, Rezaei M, Sintchak MD, Talreja T, Thomas MP, Traore T, Vyskocil S, Weatherhead GS, Yu J, Zhang J, Dick LR, Claiborne CF, Rolfe M, Bolen JB, Langston SP. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009 Apr 9;458(7239):732-6.