Before you decide to fly into Frankfurt and take separate transportation from there, check the train schedule for time and cost. We're going to Prague at the beginning of September and the cost of a non-stop flight to Frankfurt was inexpensive but transportation (flight or train) to Prague was not feasible.
For our dates, flying into London and then on to Prague on a separate ticket was much cheaper than buying anything directly into Prague. We have a flight to London on United and then a flight to Prague on BA. There is over a 4 hour layover but we saved a lot of money. The last time we did this, BA was really great when our flight from SFO was late, so I have no reservations about doing it again. Granted, we do have travel insurance for medical the other coverage was not much more, so we are covered for missed connections.
For other dates, we found that there were connections through Frankfurt as one ticket (check Kayak and United using Star Alliance options) as well as through London that were cheaper than booking separately. Also, I have found that sometimes BA tickets are cheaper on the American Airlines website. Another option is checking where easyJet has connections to Prague and see if you can get a coordinating flight.