I am using the Helix LT for a year now in different ways with amp modeling, great for recording my songs! But also I got it working very well into a tube amp's clean channel. I did 4cable also even with switching between real amp and modeling amp, but I like the simplicity of getting straight in.
Setting the amp at a lovable tone with a clean sound I've got the basics there ( Amp is a VHT Pittbull 45 btw, a 'modern' Voxy amp)
From there I add my fav. distortions without too much gain, so I can gainstage them, turn the knobs a little to make a nice tone. I add my fav. delays and modulations verbs etc..
Add a volume booster(EQ/Compressor) for leads áfter your drives. keep all the FX volumes in control on rehearsal volume! (Fletcher Munson)
Don't try to get an impressive sound at bedroom levels, unless you need it to sound at that volume.
Hope it helps a bit.