We observed a significant improvement in binding affinity for only one chemical series where two analogs (CACHE2-HO_1421_29 and CACHE2-HO_1421_27) showed a 3-fold increase in binding affinity compared with the Round 1 hit (CACHE_1421_62). The other exception is CACHE2-HO_1431_6 but it is a very distant analog of the parent molecule. The limited improvement seen in Round 2 may reflect a limitation in the commercial availability of analogs. Indeed, dedicated chemistry is typically preferred for the design of highly customized molecules. A mechanism to mitigate this effect could be to focus Round 1 screening on compounds richly derivatized in commercial catalogs. We expect that such an approach will become more attractive in the future, as commercial libraries keep growing.