Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models.

ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit.

Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance.

The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties.

Expeditious Access to Functionalized Tricyclic Pyrrolo-Pyridones via Tandem or Sequential C-N/C-C Bond Formations.

The facile synthesis of both saturated and unsaturated tricyclic pyrrolo-pyridones starting from a single readily available, common monocyclic reagent has been developed. An intermolecular annulation via a tandem Buchwald-Hartwig/Heck reaction led to the synthesis of β-carbolinones. The analogous semisaturated tricyclic pyrrolo-pyridones were prepared in good to excellent yields by sequential Buchwald-Hartwig and Fischer indole reactions.