Made in 1934, Manhattan Melodrama paired Powell with Myrna Loy for the very first time.

Clark Gable plays Blackie Gallagher and Powell is Jim Wade.  They grew up together, loyal buddies for all time, except Blackie's a gambler and Jim's an attorney destined for great things.  Myrna Loy, as Eleanor, starts out as Blackie's girl, but after meeting the dedicated (and law-abiding) Jim, she changes her mind about whom she loves.

The inevitable happens:  Blackie gets into trouble that even he can't get out of, and Jim Wade finds himself trapped into prosecuting his boyhood friend for murder.

 Manhattan Melodrama became famous in its day for being the movie that gangster John Dillinger came out of hiding to see and was gunned down by the police.

Anecdote: In 1938, Clark Gable and Myrna Loy were voted King and Queen of the Movies in a magazine poll.  (Powell had placed fourth.) 
The following day, Ms. Loy received a huge florist's box. Inside were bunches of old, sour grapes -- with a note from Powell that said "Congratulations from William the Fourth."