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

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 tol

SUBMITTER: Patterson CM 

PROVIDER: S-EPMC7835349 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature