Yeah, the first story I read with the Lizard in it was the Inferno tie-in waaaay back when. Todd McFarlane was still illustrating. Peter has to fight a flying shark in the Lincoln Tunnel, and then Curt Connors succumbs to the Lizard in order to fight off some demons and save his family. Of course The Lizard only complies in fighting off the demons so he can have the pleasure of killing his family himself. Spider-Man shows up to stop him at some point, I think. I just remember thinking how creepy the whole issue was, and how scary-dangerous the lizard looked. In my mind McFarlane's Lizard is still the definitive version.
Anyway, I think if they could do a good job making him very vicious as the lizard and very conflicted as Curt Connors, they could easily frame the whole film around him, and throw in the Black Cat as an interesting new character.