Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy
Claire Patterson, Srividya B. Balachander, Iain Grant, Petar Pop-Damkov, Brian D. Kelly, William McCoull, Jeremy S. Parker, Michael Giannis, Kathryn J. Hill, Francis D. Gibbons, Edward J. Hennessy, Paul D. Kemmitt, Alexander R. Harmer, Sonya Gales, Stuart Purbrick, Sean Redmond, Matthew Skinner, Lorraine Graham, J. Paul Secrist, Alwin G. Schuller, Shenghua Wen, Ammar Adam, Corinne Reimer, Justin Cidado, Martin Wild, Eric T. Gangl, Stephen E. Fawell, Jamal Saeh, Barry R. Davies, David J. Owen, Marianne Ashford
Abstract
Abstract 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.