The rapper's latest track 'My Life', which features Eminem and Maroon 5's Adam Levine, leads the official midweek tally, while last week's chart-topper will.i.am falls to two with 'Scream & Shout'.
Meanwhile, Justin Timberlake's first single in over five years 'Suit & Tie' debuts at number three, Rihanna's 'Stay' completes the top five, and One Direction climb two spots to ten with 'Kiss You'.
Further down the chart, Biffy Clyro's 'Black Chandelier' starts at number 11, Emeli Sandé's 'Clown' vaults from 23 to 14, and Adele's 'Skyfall' leaps 21 to 15 following her Golden Globes win.
Anne Hathaway's 'I Dreamed A Dream' is at 21, Matrix + Futurebound's 'Magnetic Eyes' lifts 39 to 29, and Ne-Yo's 'Forever Now' is new at 33.
On the album chart, the Les Misérables movie soundtrack climbs from four to number one, while Sandé's Our Version of Events is at two.
Elsewhere, Villagers' Awayland is new at 12, New Order's Lost Sirens starts at 14, and Adele's 21 leaps from 40 to 30.
The Official Top 40 Chart is announced every Sunday between 4pm and 7pm.
Watch the music video for 50 Cent's 'My Life' below: