2. Academic Validation
  3. Pharmacodynamics of Akt drugs revealed by a kinase-modulated bioluminescent indicator

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

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. yichisu@fudan.edu.cn.
  • 8 Department of Bioengineering, Stanford University, Stanford, CA, USA. mzlin@stanford.edu.
  • 9 Department of Neurobiology, Stanford University, Stanford, CA, USA. mzlin@stanford.edu.
  • 10 Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA. mzlin@stanford.edu.
  • 11 Department of Pediatrics, Stanford University, Stanford, CA, USA. mzlin@stanford.edu.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168915
    Akt Inhibitor
    Akt; PKA