Abstract 528P
Background
The B-cell lymphoma-2 (BCL-2) family of proteins are essential components in the intrinsic apoptosis pathway. While a primary mechanism for the removal of damaged or unwanted cells, dysregulation of this pathway is observed in many human cancers. Specifically, BCL-2 overexpression has been associated with pro-survival of multiple hematological and solid tumor malignancies. In the clinic, BCL-2 inhibitors have demonstrated impressive efficacy in hematological diseases, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL). However, development of more selective BCL-2 inhibitors is warranted as thrombocytopenia, resulting from BCL-xL inhibition, is a common adverse reaction in patients receiving the approved BCL-2 inhibitor venetoclax. ZN-d5 is a potent, selective, and orally bioavailable BCL-2 inhibitor with increased selectivity for BCL-2 vs. BCL-xL compared to venetoclax with significant nonclinical anti-tumor activity in multiple cancer models.
Methods
BCL-2 family binding affinity was measured using the BCL2scanTM ligand binding assay and homogeneous time-resolved fluorescence (HTRF). Cell proliferation in tumor cell lines and platelet viability was measured using CellTiter-Glo® (Promega). Anti-tumor efficacy was determined in xenograft models of NHL, AML, and other hematological and solid tumor types.
Results
ZN-d5 exhibits potent anti-proliferative activity across multiple tumor cell lines. Compared to venetoclax, ZN-d5 has >14x improved selectivity for BCL-2 over BCL-xL and was 4 to 5-fold less cytotoxic in a platelet viability assay, suggesting the potential for reduced thrombocytopenia in patients. In vivo, ZN-d5 induced tumor regression as a single agent in several tumor models including NHL and AML. In combination studies, ZN-d5 potentiated the antitumor efficacies of standard of care agents.
Conclusions
In summary, ZN-d5 is a promising new BCL-2 inhibitor with improved selectivity for BCL-2 vs other BCL-2 family members and demonstrates potent single-agent and combination activity in multiple in vivo tumor models. ZN-d5 is currently in phase 1 clinical trials for the treatment of NHL and AML.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Zentalis Pharmaceuticals.
Funding
Zentalis Pharmaceuticals.
Disclosure
J.R. Pinchman: Financial Interests, Personal, Full or part-time Employment, null: Zentalis Pharmaceuticals; Financial Interests, Personal, Stocks/Shares, null: Zentalis Pharmaceuticals; Financial Interests, Personal, Other, I am a member of Recurium IP Holdings, LLC which retains future rights to royalties and milestones associated with ZN-d5.: Recurium IP Holdings, LLC. H. Izadi: Financial Interests, Personal, Stocks/Shares: Zentalis Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment: Zentalis Pharmaceuticals. C.D. Hopkins: Financial Interests, Personal, Stocks/Shares: Zentalis Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment: Zentalis Pharmaceuticals; Financial Interests, Personal, Other,: I am a member of Recurium IP Holdings, LLC which retains future rights to royalties and milestones associated with ZN-d5.: Recurium IP Holdings, LCC. N. Ibrahim: Financial Interests, Personal, Stocks/Shares: Zentalis Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment: Zentalis Pharmaceuticals. K.D. Bunker: Financial Interests, Personal, Full or part-time Employment: Zentalis Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Pharmaceuticals; Financial Interests, Personal, Other,: I am a member of Recurium IP Holdings, LLC which retains future rights to royalties and milestones associated with ZN-d5: Recurium IP Holdings, LLC. F. Doñate: Financial Interests, Personal, Stocks/Shares: Zentalis Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment: Zentalis Pharmaceuticals. A.A. Samatar: Financial Interests, Personal, Stocks/Shares: Zentalis Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment: Zentalis Pharmaceuticals. P.Q. Huang: Financial Interests, Personal, Stocks/Shares: Zentalis Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment: Zentalis Pharmaceuticals; Financial Interests, Personal, Other, I am a member of Recurium IP Holdings, LLC which retains future rights to royalties and milestones associated with ZN-d5: Recurium IP Holdings, LCC.