Phosphatidylinositol 5-phosphate
4-kinases (PI5P4Ks) are important
molecular players in a variety of diseases, such as cancer. Currently
available PI5P4K inhibitors are reversible small molecules, which
may lack selectivity and sufficient cellular on-target activity. In
this study, we present a new class of covalent pan-PI5P4K inhibitors
with potent biochemical and cellular activity. Our designs are based
on THZ-P1-2, a covalent PI5P4K inhibitor previously developed in our
lab. Here, we report further structure-guided optimization and structure–activity
relationship (SAR) study of this scaffold, resulting in compound 30, which retained biochemical and cellular potency, while
demonstrating a significantly improved selectivity profile. Furthermore,
we confirm that the inhibitors show efficient binding affinity in
the context of HEK 293T cells using isothermal CETSA methods. Taken
together, compound 30 represents a highly selective pan-PI5P4K
covalent lead molecule.