Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,

Abstract

PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.

A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth

“…The high selectivity of compound 1 might stem from different number or proximity of the surface-accessible lysine residues between ENL and AF9 [ 57 ]. Sequence alignment of ENL and AF9 (Additional file 1 : Figure S9) indicates ENL possesses 6 more lysine residues in a short peptide segment 175–192 in its intrinsically disordered region, while few different lysine residues are in the conserved YEATS and AHD domains.…”

Strategies to Reduce the On‐Target Platelet Toxicity of Bcl‐xL Inhibitors: PROTACs, SNIPERs and Prodrug‐Based Approaches

“…Further experiments on VHL‐knock out models and preincubated cells with proteasome inhibitors ( MLN4924 and MG132 ), abrogated the Bcl‐x L as well as Bcl‐2 degradation activity of S ‐ 753 b , indicating the proteasomal mediated Bcl‐2/Bcl‐x L degradation mechanism. Compared to the other dual Bcl‐x L /Bcl‐2 degrader ( Pz703b ) as shown in Figure7 A, 753 b shows a relatively lower therapeutic index towards platelets [39] …”

“… Ternary complexes of DT2216 (A), 753b (B), and superpose of DT2216 / 753 b (C). Reproduced with permission from Lv et al [39] . Copyright 2021 Nature Publishing Group.…”

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

“…Then, Zhou and Zheng group obtained a series of degraders based on DT2216 and the binding mode of ABT-263 in Bcl-xl, which was linked the VHL to the methyl group of dimethylcyclohexene in ABT-263. 141 They found 81 ( 753b , Fig. 20 ) was a better dual-target degrader targeting Bcl-xl and BCL-2, it could not only induce the degradation of Bcl-xl(DC 50 = 6 nM), but also degrade BCL-2 (DC 50 = 48 nM) in 293T cells.…”