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

  • Nat Chem Biol. 2025 Feb 11. doi: 10.1038/s41589-025-01846-y.
Yan Wu  1 ,  Chenzhou Hao  2 ,  Chao Gao  3 ,  Matt Hageman  3 ,  Sungmoo Lee  2 ,  Thomas A Kirkland  4 ,  Nathanael S Gray  5  6 ,  Yichi Su  7 ,  Michael Z Lin  8  9  10  11
Affiliations
  • 1. Department of Bioengineering, Stanford University, Stanford, CA, USA.
  • 2. Department of Neurobiology, Stanford University, Stanford, CA, USA.
  • 3. Promega Corporation, San Luis Obispo, CA, USA.
  • 4. Promega Corporation, Madison, WI, USA.
  • 5. Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
  • 6. Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
  • 7. Department of Nuclear Medicine, Zhongshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China. [email protected].
  • 8. Department of Bioengineering, Stanford University, Stanford, CA, USA. [email protected].
  • 9. Department of Neurobiology, Stanford University, Stanford, CA, USA. [email protected].
  • 10. Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA. [email protected].
  • 11. Department of Pediatrics, Stanford University, Stanford, CA, USA. [email protected].
PMID: 39934397 DOI: 10.1038/s41589-025-01846-y
Abstract

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.

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