Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Research, apoptosis, Translational Research, Lymphomas, B Cell lymphoma, drug development, Diseases, Therapies, Lymphoid Malignancies, Biological Processes
BCL2A1 overexpression has been reported in many types of B cell lymphoma. Diffuse Large B Cell Lymphoma (DLBCL) patient sample analysis showed that BCL2A1 expression levels are second only to MCL1 within the anti-apoptotic family. Expression of BFL-1 was shown to be upregulated in MYC+/BCL2+ double hit lymphoma cell lines treated with the BCL-2 inhibitor, Venetoclax, in vivo. Interestingly, BFL-1 positive lymphomas are less sensitive to inhibition of BCL-2 and MCL-1. Hence, targeting BFL-1 is a rational and attractive strategy in DLBCL to improve clinical outcome.
Methods: Using hit identification screens followed by iterative structure-activity relationship (SAR) analyses and structure-based design, compound A, a first-in-class, selective BFL-1 BH3 mimetic, was identified. Compound A was evaluated using biochemical, cellular in vitro and in vivo tumor efficacy models.
Results: Compound A is a highly potent and selective compound in biochemical assays. In BFL-1 sensitive lymphoma cell lines characterized by high BFL-1 protein expression, compound A was shown to displace BAK and BIM from BFL-1, leading to downstream cleavage of caspase 3 and cell death. Interestingly, these cellular models were resistant to Venetoclax. Compound A exhibited tumor growth inhibition in an engineered BFL-1 overexpressing, MCL-1 KO human multiple myeloma xenograft model. However, in the high BFL-1 expressing SU-DHL-2 DLBCL human xenograft model, compound A did not induce significant PD (cleaved caspase 3) and efficacy in vivo.
Conclusion: First-in-class selective BFL-1 BH3 mimetics are shown to specifically inhibit cell growth of lymphoma cell lines in vitro and can induce efficacy in vivo in a BFL-1 overexpressing model. Further studies may be useful to determine whether compound A elicits anti-tumor efficacy in lymphoma alone or in combination with other anti-apoptotic agents.
Disclosures: Derks: Janssen: Current Employment. Bryan: Janssen: Current Employment, Current equity holder in publicly-traded company. Rockx: Janssen: Current Employment. Schults: Janssen: Current Employment. Verhulst: Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Pietrak: Janssen: Current Employment, Current equity holder in publicly-traded company. Maehigashi: Janssen: Current Employment, Current equity holder in publicly-traded company. Robertson: Janssen: Current Employment. DeMaria: Janssen: Current Employment. Holt: Janssen: Current Employment. Ji: Janssen: Current Employment, Current equity holder in publicly-traded company. Wong: Janssen: Current Employment. Bueters: Janssen: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Koo: Janssen: Current Employment, Current equity holder in publicly-traded company. Masure: Janssen: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Bhogal: Janssen: Current Employment, Current equity holder in publicly-traded company. Kelly: Janssen: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Mitra: Janssen: Current Employment, Current equity holder in publicly-traded company. Luistro: Janssen Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Shaffer: Janssen: Current Employment, Current equity holder in publicly-traded company. Szewczuk: Janssen: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Elsayed: Janssen: Current Employment, Current equity holder in publicly-traded company. Philippar: Janssen: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
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