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

Abdel-Rahman, S. M. & Kauffman, R. E. The integration of pharmacokinetics and pharmacodynamics: understanding dose–response. Annu. Rev. Pharmacol. Toxicol. 44, 111–136 (2004).

Article  CAS  PubMed  Google Scholar 

Onken, J. et al. Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo. Oncotarget 7, 9876–9889 (2016).

Article  PubMed  PubMed Central  Google Scholar 

Conway, J. R. W. et al. Monitoring Akt activity and targeting in live tissue and disease contexts using a real-time Akt-FRET biosensor mouse. Sci. Adv. 9, eadf9063 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Turner, N. et al. Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial. Breast Cancer Res. Treat. 191, 565–576 (2022).

Article  CAS  PubMed  Google Scholar 

Altomare, D. A. & Testa, J. R. Perturbations of the Akt signaling pathway in human cancer. Oncogene 24, 7455–7464 (2005).

Article  CAS  PubMed  Google Scholar 

Cheng, J. Q., Lindsley, C. W., Cheng, G. Z., Yang, H. & Nicosia, S. V. The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 24, 7482–7492 (2005).

Article  CAS  PubMed  Google Scholar 

Manning, B. D. & Toker, A. Akt/PKB signaling: navigating the network. Cell 169, 381–405 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Martorana, F. et al. Akt inhibitors: new weapons in the fight against breast cancer. Front. Pharmacol. 12, 662232 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Nitulescu, G. M. et al. Akt inhibitors in cancer treatment: the long journey from drug discovery to clinical use (review). Int. J. Oncol. 48, 869–885 (2016).

Article  CAS  PubMed  Google Scholar 

FDA approves capivasertib with fulvestrant for breast cancer. US Food and Drug Administration https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer (2023).

Turner, N. C. et al. Capivasertib in hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 388, 2058–2070 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang, L. et al. Molecular imaging of Akt kinase activity. Nat. Med. 13, 1114–1119 (2007).

Article  CAS  PubMed  Google Scholar 

Hall, M. P. et al. Engineered luciferase reporter from a deep sea shrimp utilizing a novel imidazopyrazinone substrate. ACS Chem. Biol. 7, 1848–1857 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dixon, A. S. et al. NanoLuc complementation reporter optimized for accurate measurement of protein interactions in cells. ACS Chem Biol. 11, 400–408 (2016).

Article  CAS  PubMed  Google Scholar 

Masters, S. C., Yang, H., Datta, S. R., Greenberg, M. E. & Fu, H. 14-3-3 inhibits Bad-induced cell death through interaction with serine-136. Mol. Pharmacol. 60, 1325–1331 (2001).

Article  CAS  PubMed  Google Scholar 

Tzivion, G., Dobson, M. & Ramakrishnan, G. FoxO transcription factors; regulation by Akt and 14-3-3 proteins. Biochim. Biophys. Acta 1813, 1938–1945 (2011).

Article  CAS  PubMed  Google Scholar 

Wu, Y. et al. Kinase-modulated bioluminescent indicators enable noninvasive imaging of drug activity in the brain. ACS Cent. Sci. 9, 719–732 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Su, Y. et al. Novel NanoLuc substrates enable bright two-population bioluminescence imaging in animals. Nat. Methods 17, 852–860 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Davies, B. R. et al. Preclinical pharmacology of AZD5363, an inhibitor of Akt: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol. Cancer Ther. 11, 873–887 (2012).

Article  CAS  PubMed  Google Scholar 

She, Q. B. et al. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS ONE 3, e3065 (2008).

Article  PubMed  Google Scholar 

Li, X. et al. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget 7, 33440–33450 (2016).

Article  PubMed  Google Scholar 

Niessner, H. et al. Targeting hyperactivation of the Akt survival pathway to overcome therapy resistance of melanoma brain metastases. Cancer Med. 2, 76–85 (2013).

Article  CAS  PubMed  Google Scholar 

Kempska, J. et al. Impact of AKT1 on cell invasion and radiosensitivity in a triple negative breast cancer cell line developing brain metastasis. Front. Oncol. 13, 1129682 (2023).

Article  CAS  PubMed  Google Scholar 

Chong, Z. Z., Shang, Y. C., Wang, S. & Maiese, K. A critical kinase cascade in neurological disorders: PI3K, Akt, and mTOR. Future Neurol. 7, 733–748 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ippen, F. M. et al. Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases. Neuro Oncol. 21, 1401–1411 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Brighi, C. et al. Comparative study of preclinical mouse models of high-grade glioma for nanomedicine research: the importance of reproducing blood–brain barrier heterogeneity. Theranostics 10, 6361–6371 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Su, Y. et al. An optimized bioluminescent substrate for non-invasive imaging in the brain. Nat. Chem. Biol. 19, 731–739 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Roche finally drops curtain on AKT drug ipatasertib. Pharmaphorum https://pharmaphorum.com/news/roche-finally-drops-curtain-akt-drug-ipatasertib (2023).

Blake, J. F. et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J. Med. Chem. 55, 8110–8127 (2012).

Article  CAS  PubMed  Google Scholar 

Fong, C. W. Permeability of the blood–brain barrier: molecular mechanism of transport of drugs and physiologically important compounds. J. Membr. Biol. 248, 651–669 (2015).

Article  CAS  PubMed  Google Scholar 

van De Waterbeemd, H., Smith, D. A., Beaumont, K. & Walker, D. K. Property-based design: optimization of drug absorption and pharmacokinetics. J. Med. Chem. 44, 1313–1333 (2001).

Article  PubMed  Google Scholar 

Lin, J. et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin. Cancer Res. 19, 1760–1772 (2013).

Article  CAS  PubMed 

Comments (0)

No login
gif