A combination of thumb key layout optimisation and practice.
Put the most used keys where the thumbs rest naturally.
On my board, my most used thumb keys are space, shift and backspace. My right thumb rests on the space key and I use space with my right thumb normally, so that took no time. Left thumb rests on shift and that also was very fast. Took a bit longer to train backspace, but was quite intuitive and I got comfortable with it soon.
My other thumb keys are layer / Fn, enter, tab, ctrl and alt. Those aren't used as much, so training them takes a bit longer, but they don't slow me down at least.
It's harder with something like the Maltron layout which places the letter E on a thumb key, but then again, it's probably just part of learning the whole new layout on one of those.
IMHO, shift definitely belongs on a thumb key. Pressing and holding a modifier with your pinkie while typing is horribly unergonomic, no matter how you look at it. So if the board you have is programmable, try putting shift in the "mirror" position to space (other thumb), with backspace also in an easy-to-reach position.
Unlearning old habits is probably the biggest hurdle to getting used to a new layout.
