The short answer is no; not if you want to keep playing it, anyway. Compression is really only useful for storage. As discussed above, you might be able to bring the size down somewhat by stripping out content from the disc image, depending on whether there's anything in the game that's not needed or that you could do without. As an example, a lot of Wii games will store all their FMV content twice: once for 576i/50Hz mode, and once for 480i or 480p/60Hz. This is true even for a lot of NTSC games, so if you get lucky there might be an entire batch of FMVs which you can remove without impacting the game experience. Beyond that, you're getting into more complicated and uglier areas like converting the audio to mono, etc.
Ultimately though, there's no "hands free" way to achieve what you're looking for; if you really want it smaller you'll have to get your hands dirty and the results may not even be worth it.