Design, Synthesis and Evaluation of WD-repeat containing protein 5 (WDR5) degraders

Doelle, A.; Adhikari, Bikash; Kraemer, Andreas; Weckesser, Janik; Berner, Nicola; Berger, Lena M.; Diebold, Mathias; Szewczyk, Magdalena M.; Baršytė-Lovejoy, Dalia; Arrowsmith, C.H.; Gerbel, J.; Loehr, F.; Doetsch, V.; Eilers, Martin; Heinzlmeir, S.; Kuester, B.; Sotriffer, Christoph A.; Wolf, Elmar; Knapp, S.

doi:10.1101/2021.04.12.439490

Cited by 2 publications

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“…119 Contrary to the occupancy-driven binding event of small molecule inhibitors, PROTACs rely on an event-driven mechanism of action, making them attractive for undruggable proteins (like transcription factors) 120 or proteins with scaffolding functions. 112,121 Due to the different MoA, PROTACs harboring a weak affinity ligand for the target protein can also result in an effective binder. [122][123] In comparison to nucleic acid-based approaches that suppress protein synthesis, PROTAC-mediated degradation works independently from protein half-life times.…”

Section: Proteolysis Targeting Chimeramentioning

confidence: 99%

Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

et al. 2021

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In total, more than 700 proteins regulate chromatin function 18,[22][23] and they are often part of multi-domain protein complexes. Beside the catalytic subunit that controls chromatin accessibility, also subunits that recognize and interact with epigenetic modifications are crucial components of histone modifying complexes. 2 Despite the three classes of epigenetic readers, erasers, and writers, also epigenetic movers, shapers and insulators interact with chromatin structure. [24][25] Proteins that recognize post-translational modifications are classified as epigenetic readers. 26 Well-studied protein families for epigenetic readers are, e.g., bromodomains (BRDs), which recognize acetylated lysine residues. The BRDs have been extensively studied and successfully drugged in cancer treatment. 26 In Table 1, the bromodomain BRD4 of the bromodomain and extraterminal domain (BET) family is listed due to its prominent role in super-enhancers (SEs) organization and regulation of oncogene expression in cancer. 27 Targeting BRD4 by inhibiting the acetyl-lysine binding site with small molecules, e.g., the first BRD targeting inhibitor (JQ1), was shown to be an effective strategy for cancers like the aggressive NUT midline carcinoma (NMC). [28][29] Beside the outstanding role of BRD4, other BRDs are involved as epigenetic readers in various nucleosome remodeling complexes: in the ATP-dependent human complexes BAF (BRG1/BRMassociated factor) and PBAF (polybromo-associated BAF factor), two bromodomains, SMARCA2/ 4 (SWI/SNF-related, matrix-associated actin-dependent regulator of chromatin, subfamily A2/ 4), perturbate with the core subunits BRG1/BRM histone-DNA contacts. [30][31][32] Mutations in BAF components are one of the most frequently observed genetic alteration in cancer. [33][34] demonstrated how mutations and misregulations of histone lysine methyltransferases (KMTs), demethylases and methyl-lysine-binding proteins are connected to various diseases, thus making them effective therapeutic targets for cancer treatments. [46][47] The histone demethylation process is carried out by lysine demethylases like LSD1 48 and the JARID1 familiy 49 epigenetic erasers that are known to be perturbed in cancer, as previously listed in Table 1. Equally involved in cancer formation is the class of histone lysine methyltransferases (KMTs) which are categorized as epigenetic writers. KMTs comprise proteins like MLL1-3 and SET1D which are relevant drug targets, as shown in the non-exhaustive list in Table 1. Within histone lysine methylation, H3K4 methylation is an evolutionary conserved motif that marks active gene transcription 50-51 and is highly enriched at the promotor region and transcription start site. 51 The family of Histone lysine Methyltransferases and its adaptor proteins are described in the following chapter.while the pink colored c-Myc peptide MbIIIb binds to WDR5 on a shallow cleft on the surface, the so called WBM side (pdb entry: 3eg6 and 4y7r).WDR5 has emerged as a promising drug target for anti-cancer therapies as i...

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Section: Proteolysis Targeting Chimeramentioning

confidence: 99%

Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

et al. 2021

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“…[25] Rosetta has become one of the most widely used proteinprotein docking techniques in TPD. Alternative tools applied in TPD include PatchDock, [96][97] FRDOCK, [98][99] MOE packages, [100][101][102][103] ClusPro, [104] and LightDock. [105] The in silico determination of ternary complexes calls for a thorough understanding of protein-protein conformations.…”

Section: Protein-protein Dockingmentioning

confidence: 99%

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

2023

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Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a promising alternative and complement to available therapeutic interventions (e. g., inhibitors). Degraders rely on protein binding instead of inhibition and, hence, they hold the promise to broaden the druggable proteome. Biophysical and structural biology approaches have been the cornerstone of understanding and rationalizing degraderinduced ternary complex formation. Computational models have now started to harness the experimental data from these approaches with the aim to identify and rationally help design new degraders. This review outlines the current experimental and computational strategies used to study ternary complex formation and degradation and highlights the importance of effective crosstalk between these approaches in the advancement of the targeted protein degradation (TPD) field. As our understanding of the molecular features that govern druginduced interactions grows, faster optimizations and superior therapeutic innovations for TPD and other proximity-inducing modalities are sure to follow.

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Design, Synthesis and Evaluation of WD-repeat containing protein 5 (WDR5) degraders

Cited by 2 publications

References 52 publications

Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

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