Pharmacodynamics of Akt drugs revealed by a kinase-modulated bioluminescent indicator

Measuring pharmacodynamics (PD)-the biochemical effects of drug dosing-and correlating them with therapeutic efficacy in animal models is crucial for the development of effective drugs but traditional PD studies are labor and resource intensive. Here we developed a kinase-modulated bioluminescent indicator (KiMBI) for rapid, noninvasive PD assessment of Akt-targeted drugs, minimizing drug and animal use. Using KiMBI, we performed a structure-PD relationship analysis on the brain-active Akt inhibitor ipatasertib by generating and characterizing two novel analogs. One analog, ML-B01, successfully inhibited Akt in both the brain and the body. Interestingly, capivasertib, ipatasertib and ML-B01 all exhibited PD durations beyond their pharmacokinetic profiles. Furthermore, KiMBI revealed that the PD effects of an Akt-targeted proteolysis-targeting chimera degrader endured for over 3 days. Thus, bioluminescence imaging with Akt KiMBI provides a noninvasive and efficient method for in vivo visualization of the PD of Akt inhibitors and degraders.