528P Discovery of ZN-d5, a potent BCL-2 inhibitor with improved selectivity for BCL-2

The B-cell lymphoma-2 (BCL-2) family of proteins are essential components in the intrinsic apoptosis pathway. While a primary mechanism for removal damaged or unwanted cells, dysregulation this pathway is observed many human cancers. Specifically, BCL-2 overexpression has been associated with pro-survival multiple hematological and solid tumor malignancies. In clinic, inhibitors have demonstrated impressive efficacy diseases, including chronic lymphocytic leukemia (CLL), acute myeloid (AML), non-Hodgkin lymphoma (NHL). However, development more selective warranted as thrombocytopenia, resulting from BCL-xL inhibition, common adverse reaction patients receiving approved inhibitor venetoclax. ZN-d5 potent, selective, orally bioavailable increased selectivity vs. compared to venetoclax significant nonclinical anti-tumor activity cancer models. binding affinity was measured using BCL2scanTM ligand assay homogeneous time-resolved fluorescence (HTRF). Cell proliferation cell lines platelet viability CellTiter-Glo® (Promega). Anti-tumor determined xenograft models NHL, AML, other types. exhibits potent anti-proliferative across lines. Compared venetoclax, >14x improved over 4 5-fold less cytotoxic assay, suggesting potential reduced thrombocytopenia patients. vivo, induced regression single agent several NHL AML. combination studies, potentiated antitumor efficacies standard care agents. summary, promising new vs members demonstrates single-agent vivo currently phase 1 clinical trials treatment