Amorphous solid dispersions: Utilization and challenges in preclinical drug development within AstraZeneca.

The poor aqueous solubility of many active pharmaceutical ingredients (APIs) dominates much of the early drug development portfolio and poses a major challenge in pharmaceutical development. Polymer-based amorphous solid dispersions (ASDs) are becoming increasingly common and offer a promising formulation strategy to tackle the solubility and oral absorption issues of these APIs. This review discusses the design, manufacture, and utilisation of ASD formulations in preclinical drug development, with a key focus on the pre-formulation assessments and workflows employed at AstraZeneca.

Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase.

Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines. In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.