Abstract
PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related protein families remain elusive. Here, we generate isoform-selective PROTACs for the p38 MAPK family using a single warhead (foretinib) and recruited E3 ligase (von Hippel-Lindau). Based on their distinct linker attachments and lengths, these two PROTACs differentially recruit VHL, resulting in degradation of p38α or p38δ. We characterize the role of ternary complex formation in driving selectivity, showing that it is necessary, but insufficient, for PROTAC-induced substrate ubiquitination. Lastly, we explore the p38δ:PROTAC:VHL complex to explain the different selectivity profiles of these PROTACs. Our work attributes the selective degradation of two closely-related proteins using the same warhead and E3 ligase to heretofore underappreciated aspects of the ternary complex model.
Highlights
PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation
Shortening the linker length in the “phenyl series” down to 10 atoms produced a PROTAC with strong capacity to degrade p38δ selectively: SJFδ degrades p38δ with a DC50 of 46.17 ± 9.85 nM and a Dmax of 99.41 ± 3.31% (Figs. 1c, d) but does not degrade p38α, β, or γ
Starting with the kinase inhibitor foretinib, which exhibits pan-selectivity towards the p38 MAPK family, as the targeting warhead, we developed PROTACs – SJFα and SJFδ – that differentially recruit von Hippel-Lindau (VHL), and in doing so achieve distinct p38α/p38δ degradation profiles
Summary
PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. PROteolysis-TArgeting Chimeras (PROTACs) have emerged as a promising therapeutic approach that targets proteins to the proteasome for degradation to overcome occupancy-based active site limitations, thereby expanding the potential “druggable proteome”[8,9,10,11,12,13] In their simplest form, PROTACs couple a small molecule binder of a target protein (warhead) to an E3 ubiquitin ligaserecruiting moiety via an intervening chemical linker[14,15,16,17]. These degraded substrate proteins included even those with only weak binding affinity for the PROTAC (e.g., p38 Mitogen-activated protein kinase [MAPK]), demonstrating how compensatory PPIs afforded by the substrate:PROTAC:ligase interface provide an added layer of selectivity and affinity for target proteins[36,37,39]
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