Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy

• Published in: Communications biology Vol. 4; no. 1; pp. 1 - 14
• Main Authors: Patterson, Claire M., Balachander, Srividya B., Grant, Iain, Pop-Damkov, Petar, Kelly, Brian, McCoull, William, Parker, Jeremy, Giannis, Michael, Hill, Kathryn J., Gibbons, Francis D., Hennessy, Edward J., Kemmitt, Paul, Harmer, Alexander R., Gales, Sonya, Purbrick, Stuart, Redmond, Sean, Skinner, Matthew, Graham, Lorraine, Secrist, J. Paul, Schuller, Alwin G., Wen, Shenghua, Adam, Ammar, Reimer, Corinne, Cidado, Justin, Wild, Martin, Gangl, Eric, Fawell, Stephen E., Saeh, Jamal, Davies, Barry R., Owen, David J., Ashford, Marianne B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-01-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/51; 14/5; 59/5; 631/154/152; 631/67/1059/153; 631/67/1059/602; 692/4028/67/1059/602; 692/4028/67/1990; Bcl-2 protein; Bcl-x protein; Biology; Biomedical and Life Sciences; Cancer therapies; Drug development; Life Sciences; Lysine; Mathematical models; Physicochemical properties; Toxicity; Tumors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-01631-8

Dual Bcl-2/Bcl-x
L
inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-x
L
inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-x
L
inhibitor into clinical development.
Claire Patterson et al. present the design and development of AZD0466, a drug-dendrimer conjugate, and use preclinical and mathematical models to determine the optimal release rate of the drug from the dendrimer carrier for maximal therapeutic index in terms of anti-tumour efficacy and cardiovascular tolerability. This study identifies this promising dual Bcl-2/Bcl-x
L
inhibitor for progression to clinical development.