Preprint Watch 2026-09-18: 2 Clinical Failures Flagged for BCL2 | Claidex

Claidex Preprint Watch

doi:10.1101/2025.08.14.670414

Preprint WatchModerateSeptember 18th, 2026

Cul5Wsb2 uses BCL2 proteins as co-receptors to target Bim for degradation.

Vaysse-Zinkhofer, W.; Alcindor, E.; Garaffo, N.; Toczyski, D. P.

Anti-apoptotic BCL2 family proteins act as co-receptors that recruit BIM to the CUL5-WSB2 ubiquitin ligase for degradation, with WSB2 recognizing a motif conserved across BCL-XL, BCL-W and BCL2 but not MCL1, and engaging the MCL1-BIM dimer through a separate interface.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint places anti-apoptotic BCL2 proteins upstream of BIM turnover rather than only in direct sequestration of it, which changes what BCL2 inhibition is expected to do to the free pro-apoptotic pool. Claidex holds two BCL2 claims, both venetoclax programs in acute myeloid leukemia. One was stopped as a Phase 3 post-transplant maintenance program for strategic reasons (venetoclax-azacitidine-bcl2-aml-post-transplant-maintenance-phase3-strategic-termination) and one was stopped at a Phase 2 interim for lack of efficacy in frontline induction for secondary acute myeloid leukemia (venetoclax-flag-clag-bcl2-secondary-aml-frontline-induction-phase2-interim-termination). The preprint reports a degradation route in which BCL-XL, BCL-W and BCL2 route BIM to CUL5-WSB2, and a separate interface for MCL1. If that holds in leukemic cells, the level of free BIM released by a BH3 mimetic depends on ligase activity as well as on binding displacement, which is one more variable between target engagement and apoptosis. The claim is biochemical and has no clinical endpoint attached, so it is flagged as context for BCL2 programs rather than as a contradiction of either terminated trial.

Abstract excerpt

Anti-apoptotic BCL2 family proteins (e.g. BCL-XL) protect cells by binding and inhibiting pro-apoptotic proteins (e.g. BIM). Although CUL5WSB2 was linked to apoptosis regulation, its substrate and mechanism were unknown. We find that BCL2 proteins recruit BIM to CUL5WSB2 for degradation. WSB2 recognizes BCL-XL through a motif conserved between BCL-XL, BCL-W and BCL2, but not MCL1. Disruption of this interaction through mutation of either BCL-XL or WSB2 blocks the binding of WSB2 to the BCL-XL/BIM dimer. WSB2 also associates with the MCL1/BIM dimer through a separate WSB2 interface, suggesting that WSB2 has evolved independent two means to target BIM. While WSB2 is not essential in most cells, it is essential in cells derived from tumors of the nervous system, and knockdown of WSB2 in these lines causes death and apoptosis. This work uncovers a novel mechanism of apoptosis regulation, with implications for developing therapies against neuroblastomas and other cancers reliant on this pathway for survival.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.