TMX-4153

TMX-4153 is a well-characterized and highly potent chemical probe for studying the biological role and therapeutic potential of PIP4K2C. It exhibits nanomolar binding affinity (KD = below 45 nM) and high degradation efficiency (Dmax = 91%, DC50 = 24 nM) in MOLT4 cells. Notably, TMX-4153 demonstrates exceptional selectivity, with minimal off-target activity across the kinome and proteome. As a bivalent degrader that recruits the VHL E3 ligase, TMX-4153 is particularly suited for targeting non-catalytic functions of PIP4K2C, addressing its proposed scaffolding role. This mechanistic approach distinguishes it from traditional inhibitors and enhances its value as a probe for functional studies. While TMX-4153 shows some cell-type variability in degradation efficiency and moderate permeability, it remains a highly promising tool for dissecting PIP4K2C biology. Further optimization could improve its pharmacokinetics and broaden its applicability.

TMX-4153 is a potent and selective degrader of PIP4K2C. Selectivity was assessed by a kinome-screen as well as proteomics.