Bulky PP1 analogs exert cellular effects independently from analog-sensitive kinase inhibition

To circumvent the general lack of selectivity of protein kinase inhibitors, a chemical genetics approach has been developed to allow the selective targeting of engineered kinases by bulky ATP analogs, most of which derived from the pyrazolo[3,4-d]pyrimidine 1 (PP1) inhibitor. Although designed to selectively inhibit so-called analog-sensitive (AS) kinases presenting enlarged active sites, bulky PP1 analogs were shown to inhibit a number of wild-type protein kinases in vitro. Here, we examine the