Optimization of a “bump-and-hole” approach to allele-selective BET bromodomain inhibition

Runcie, Andrew C.; Zengerle, Michael; Chan, Kwok-Ho; Testa, Andrea; Beurden, L.V.; Baud, Matthias G. J.; Epemolu, Ola; Ellis, Catherine; Read, Kevin D.; Coulthard, V.; Brien, Alex; Ciulli, A.

doi:10.1039/c7sc02536j

Cited by 40 publications

(70 citation statements)

References 60 publications

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“…Interestingly, the clash with Leu387 is similar to that exploited in our bump-and-hole study for the same residue (Figure 3 B). [29,30] The enhanced discrimination between BD1 and BD2 could potentially be attributed to differences in the ZA-loop of BD1s compared to BD2s. Sequence alignment of the six bromodomains revealed an additional proline (Pro397) in BD1 which could limit the ability of the BD1s to accommodate the extra linker present in macroPROTAC-1 (Supporting Information, Figure S7).…”

Section: Methodsmentioning

confidence: 99%

Structure-Based Design of a Macrocyclic PROTAC

Testa¹,

Hughes²,

Lucas³

et al. 2019

Preprint

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Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to design enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC based on co-crystal structure of a parent linear molecule, by adding a cyclizing linker. A co-crystal structure of the macrocyclic PROTAC bound in a ternary complex with VHL and Brd4 validated the rational design and identified new interactions formed by the new linker. Biophysical studies revealed that the macrocycle selectively discriminated the second against the first bromodomains of BET proteins, and is a potent Brd4 degrader. Macrocyclization provides a viable strategy to induce protein-protein complexes and protein degradation inside cells.

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Section: Methodsmentioning

confidence: 99%

Structure-Based Design of a Macrocyclic PROTAC

Testa¹,

Hughes²,

Lucas³

et al. 2019

Preprint

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“…FRAP‐Studien zeigten, dass bereits die Blockade von BRD4(1) ausreicht, um BRD4 vom Chromatin zu verdrängen. Diese spezielle Strategie kann dazu beitragen, ein tieferes Verständnis für die Bedeutung der einzelnen BET‐Bromodomänen im zellulären Kontext zu erlangen . Law et al.…”

Section: Biochemische Techniken Zur Untersuchung Von Bromodomänenunclassified

Chemische Epigenetik: der Einfluss chemischer und chemo‐biologischer Techniken auf die Zielstruktur‐Validierung von Bromodomänen

Schiedel¹,

Moroglu²,

Ascough³

et al. 2019

Angewandte Chemie

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Viele Disziplinen befassen sich gegenwärtig mit Epigenetik, da diese von Bedeutung für viele biologische Vorgänge und pathologische Zustände ist. Auf molekularer Ebene fußen epigenetische Prozesse auf Modifizierungen in Nukleinbasen der DNA und RNA und/oder posttranslationalen Modifizierungen (PTMs) von Histonproteinen. Die Hinweise mehren sich, dass diese Modifikationen einer dynamischen Regulation unterliegen, mit einer zum Teil bereits identifizierten zellulären Maschinerie, die der Modulation und Interpretation dieser Markierungen dient. Wir konzentrieren uns hier auf Bromodomänen, die an acetylierte Lysinreste (KAc) binden. Fortschritte auf dem Gebiet der Bromodomänen und ihrer Liganden werden von vielen Disziplinen beflügelt, wobei der Chemie und der chemischen Biologie eine besondere Rolle zukommt. Hier werden die chemischen und chemo‐biologischen Schlüsseltechniken diskutiert, mit deren Hilfe Bromodomänen erforscht und Liganden der Bromodomänen entwickelt werden konnten – unabdingbare Voraussetzungen für die Validierung der Bromodomäne als therapeutisch sinnvolle Zielstruktur.

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“…We used this new system to dissect individual roles of BD1 vs. BD2 in Brd4 and the other BET proteins and showed that while the BD1 is necessary and sufficient for chromatin binding, the BD2 plays a role in transcriptional regulation. 24,25 Our previous approaches for incorporation of an alkyl "bump" into the I-BET scaffold involved alkylation of a potassium enolate to afford bumped I-BET derivatives with undesired diastereoselectivity and in low yields ( Fig. 2A).…”

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confidence: 99%

“…Due to the use of potassium hexamethyldisilazide (KHMDS) for the enolization, and the need of an epimerisation step at such a late stage of the synthesis, the products are racemic and require chiral separation to isolate the eutomers. [24][25][26] Separation of the enantiomers can be costly (up to £1000 for <150 mg of racemate) and leads to loss of material during the separation.…”

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confidence: 99%

“…We also provide unambiguous chemical evidence to the absolute stereochemistry of the active allele-specific ligand, previously only assumed based on cocrystal structures. 25 Our first efforts to alkylate (+)-JQ1 directly proved unsuccessful, likely due to the steric hindrance caused by the tertbutyl ester. Conversion from the tert-butyl to a methyl ester was required to allow for the introduction of the bump.…”

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confidence: 99%

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