Structural Insights into PROTAC-Mediated Degradation of Bcl-xL

Chung, Chun‐wa; Han, Dongmei; Fernández, Esther; Tinworth, Christopher P.; Churcher, Ian; Cryan, Jenni; Denyer, Jane; Harling, John D.; Konopacka, Agnieszka; Queisser, Markus A.; Tame, Christopher J.; Watt, Gillian F.; Jiang, Fan; Qian, Dongming; Benowitz, Andrew B.

doi:10.1021/acschembio.0c00266

Cited by 64 publications

(53 citation statements)

References 24 publications

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“…It is worth noting that, to the best of our knowledge, only a very limited number of degrader ternary complex structures have been reported to date (39,(42)(43)(44)(45)(46). Structure-based design to generate more effective degraders is even rarer.…”

Section: Discussionmentioning

confidence: 99%

A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models

Kottur

et al. 2021

Sci. Transl. Med.

111

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Interactions between WD40 repeat domain protein 5 (WDR5) and its various partners such as mixed lineage leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in human cancers. However, inhibitors that block protein-protein interactions (PPIs) between WDR5 and its binding partners exhibit modest cancer cell killing effects and lack in vivo efficacy. Here, we present pharmacological degradation of WDR5 as a promising therapeutic strategy for treating WDR5-dependent tumors and report two high-resolution crystal structures of WDR5degrader-E3 ligase ternary complexes. We identified an effective WDR5 degrader via structure-based design and demonstrated its in vitro and in vivo antitumor activities. On the basis of the crystal structure of an initial WDR5 degrader in complex with WDR5 and the E3 ligase von Hippel-Lindau (VHL), we designed a WDR5 degrader, MS67, and demonstrated the high cooperativity of MS67 binding to WDR5 and VHL by another ternary complex structure and biophysical characterization. MS67 potently and selectively depleted WDR5 and was more effective than WDR5 PPI inhibitors in suppressing transcription of WDR5-regulated genes, decreasing the chromatin-bound fraction of MLL complex components and c-MYC, and inhibiting the proliferation of cancer cells. In addition, MS67 suppressed malignant growth of MLL-rearranged acute myeloid leukemia patient cells in vitro and in vivo and was well tolerated in vivo. Collectively, our results demonstrate that structure-based design can be an effective strategy to identify highly active degraders and suggest that pharmacological degradation of WDR5 might be a promising treatment for WDR5-dependent cancers.

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Section: Discussionmentioning

confidence: 99%

A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models

Kottur

et al. 2021

Sci. Transl. Med.

111

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“…Thelargest number of VHL ternary complex structures have been reported from bromodomaincontaining proteins,s uch as BRD4 [29b] and SMARCA4, [31] with an additional structure of an on-bromodomain protein also having been recently disclosed. [32] Theh igh ternary complex cooperativity induced by GSK215 can be explained by many neo-interactions between FAKa nd VHL that occur at both ends of the PROTAC Angewandte molecule (Figure 4b). As expected, the FAKb inding moiety of the PROTACi scompletely enclosed by the FAKp rotein.…”

Section: Structure Of the Protac Ternary Complexmentioning

confidence: 99%

Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs

et al. 2021

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Focal adhesion kinase (FAK) is ak ey mediator of tumour progression and metastasis.T od ate,c linical trials of FAKi nhibitors have reported disappointing efficacy for oncology indications.W er eport the design and characterisation of GSK215, ap otent, selective,F AK-degrading Proteolysis Targeting Chimera (PROTAC)b ased on ab inder for the VHL E3 ligase and the knownF AK inhibitor VS-4718. Xray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice,asingle dose of GSK215 induced rapid and prolonged FAKd egradation, giving al ong-lasting effect on FAKl evels ( % 96 h) and am arked PK/PD disconnect. This tool PROTACmolecule is expected to be useful for the study of FAK-degradation biology in vivo,a nd our results indicate that FAKd egradation may be ad ifferentiated clinical strategy versus FAKi nhibition for the treatment of cancer.

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“…Ligase-PROTAC-target complexes have also been solved for systems that do not appear to exhibit positive cooperativity in the ternary equilibria, suggesting avenues for potential optimization strategy. The recent structure of a VCB:PROTAC6:B-cell lymphoma-extra-large (Bcl-xL) complex shows the long PEG linker of PROTAC6 is forced to adopt an extended conformation, before folding back into itself via a compact turn (Figure 4c) [57 ]. The unfavourable linker conformational energy likely surpasses any favourable induced PPIs, resulting in the negative cooperativity observed with this system.…”

Section: Protacs: Bifunctional Small Molecules Bridging Target Proteins To E3 Ligasesmentioning

confidence: 98%

“…Zoomed section shows the structure-based design of PROTAC 2 (PDB: 6HAX[56 ]) aimed at rigidifying the linker through substitution of a flexible 5-atom portion of the linker with a phenyl ring. (c) Ternary complex of VCB-PROTAC6(cyan)-Bcl-xL(lime green) (PDB: 6ZHC[57 ]). (d) Crystal structure of CRBN(violet)-DDB1 (green) complex with bound PROTAC dBET23 (cyan) and Brd4 BD1 (magenta) (PDB: 6BN7[58]).…”

mentioning

confidence: 99%