Each of the 26 letters of the alphabet can encrypt to one of the 26 letters of the alphabet. So A has 26 possible letters it can encrypt to. The next letter, letter B, can encrypt to any of the 26 letters of the alphabet except for the letter used for A. This means there are 25 possible letters that B could encrypt to. So far, the number of possible combinations is 26 x 25, or 650.

If we continue on, the total number of combinations for the entire alphabet is 26 x 25 x 24 x 23 x 22 x 21 x 20 x 19 x 18 x 17 x 16 x 15 x 14 x 13 x 12 x 11 x 10 x 9 x 8 x 7 x 6 x 5 x 4 x 3 x 2 x 1 or 26! (known as "twenty six factorial") or 403291461126605635584000000.

This is why there are 403291461126605635584000000 possible simple substitution keys.