Abbv-453: A Highly Potent and Selective Next Generation Small Molecule Inhibitor of BCL-2

Evading apoptosis is a hallmark of cancer that is achieved by altering the dynamic binding interactions between pro-survival (BCL-2, BCL-X_L, BCL-W, MCL-1, BFL-1) and pro-death (e.g., BAX, BAK, BAD, BIM, NOXA, PUMA) BCL-2 family members. BCL-2 itself plays a dominant role in survival of malignant hematologic cells; a dependency which has been exploited therapeutically as exemplified by the established clinical activity of BCL-2 inhibitors in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), multiple myeloma (MM), and acute myeloid leukemia (AML) (Fowler-Shorten et al., 2024).

ABBV-453, a next-generation BCL-2 inhibitor, was designed for enhanced molecular and biological properties to improve upon the patient experience relative to available therapies. Specifically, incorporation of macrocyclic elements into the hot-spot binding regions of BCL-2 afforded a constrained molecule with high potency, selectivity and durable in vivo activity at low doses. In vitro, ABBV-453 possesses sub-nM affinity for BCL-2 (K_I = 0.228 nM) and high selectivity over family members BCL-X_L and MCL-1. The high affinity and selectivity of ABBV-453 translates to potent cell killing activity human tumor cell lines dependent upon BCL-2, including the acute lymphocytic leukemia (ALL) cell line RS4;11 (EC₅₀ = 4.7 nM in the presence of 10% human serum), and greatly decreased activity in human tumor cell lines dependent on BCL-X_L (Molt-4 EC₅₀ = 2.85 µM) and MCL-1 (H929 EC₅₀ >10 µM) for survival. Moreover, the cellular activity of ABBV-453 is on-target and mechanism-based as demonstrated by the disruption of BCL-2:BIM complexes and the rapid activation of the intrinsic apoptosis signaling pathway (as evidenced by caspase-3-7 activation and dissipation of the inner mitochondrial membrane potential) and the caspase dependent externalization of annexin-V at the plasma membrane of ABBV-453 treated tumor cells.

Activity of ABBV-453 monotherapy was compared to other clinically relevant BCL-2 inhibitors in an in vivo subcutaneous xenograft model of ALL. ABBV-453 demonstrated superior growth inhibition of the RS4;11 xenograft compared to both sonrotoclax or lisaftoclax at equivalent doses and schedule. ABBV-453 has the potential to be the best-in-class next-generation BCL-2 inhibitor and is actively being investigated in phase 1 clinical trials in relapsed or refractory (R/R) MM (ClinicalTrials.gov ID, NCT05308654) and R/R CLL/SLL (NCT06291220).

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