Developing degraders: principles and perspectives on design and chemical space

Maple, Hannah J.; Clayden, Nat; Baron, Anne; Stacey, Callum; Felix, Robert L.

doi:10.1039/c9md00272c

Cited by 123 publications

(134 citation statements)

References 48 publications

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“…To assess the degradability of CDK4/6 by further ubiquitin ligases, we thought to address the E3 ligases IAP and MDM2, both commonly hijacked for degrader design. 46 For the former ligase, ligand 5 47 (Fig. 1) was selected, which was obtained in the course of an intensive structural evaluation of different IAP- based degraders.…”

Section: Chemistrymentioning

confidence: 99%

“…50 The resulting IAP-and MDM2-based degraders 35 and 37 are depicted in Tables 3 and S5 Previous reports on principles of PROTAC design highlighted the importance of different physiochemical properties to achieve successful degradation. 46,51,52 In order to assess activity determining physicochemical properties, we calculated molecular descriptors, i.e. the molecular weight, the topological polar surface area (TPSA), the number of rotatable bonds (NRotB), as well as hydrogen bond donors (HBD) and acceptors (HBA) of all compounds (Tables S1-S4, ESI †).…”

Section: Chemistrymentioning

confidence: 99%

“…Furthermore, the distribution coefficients (log D) were determined experimentally (Tables 1-3 and S5, ESI †) as a measure for lipophilicity. To draw structure-degradation relationships, we calculated the degrader score (Deg_S) 46 as an overall measure of CDK4/6d efficacy (Tables S1-S4, ESI †).…”

Section: Chemistrymentioning

confidence: 99%

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Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

et al. 2020

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Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

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Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

et al. 2020

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“…65 Degraders recruiting IAP were named specific and nongenetic IAP-dependent protein erasers (SNIPERs). [66][67][68][69][70][71][72][73][74][75][76] Later, von Hippel-Lindau ligands used for PROTAC design were identified by the Ciulli laboratory. [77][78][79] Concurrently, it was found that the E3 cereblon (CRBN) was the molecular target of the immunomodulatory drugs (IMiDs), such as thalidomide, pomalidomide, and lenalidomide.…”

Section: Introductionmentioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

438

414

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Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

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“…The diversity and size of the organic molecules of possible interest as drugs steadily increases as medicinal chemistry addresses ever more complex biological processes while also exploiting the expanding scope of synthetic organic chemistry. [1][2][3] Cheminformatics enables the exploitation and understanding of this diversity by describing molecules as molecular fingerprints, encoding their structural characteristics as a vector. [4,5] These fingerprints can be used for fast similarity comparisons forming the basis for structure-activity relationship studies, virtual screening, and the construction of chemical space maps.…”

Section: Introductionmentioning

confidence: 99%

One Molecular Fingerprint to Rule them All: Drugs, Biomolecules, and the Metabolome

Capecchi¹,

Probst²,

Reymond³

2020

Preprint

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Background: Molecular fingerprints are essential cheminformatics tools for virtual screening and mapping chemical space. Among the different types of fingerprints, substructure fingerprints perform best for small molecules such as drugs, while atom-pair fingerprints are preferable for large molecules such as peptides. However, no available fingerprint achieves good performance on both classes of molecules. Results: Here we set out to design a new fingerprint suitable for both small and large molecules by combining substructure and atom-pair concepts. Our quest resulted in a new fingerprint called MinHashed atom-pair fingerprint up to a diameter of four bonds (MAP4). In this fingerprint the circular substructures with radii of r = 1 and r = 2 bonds around each atom in an atom-pair are written as two pairs of SMILES, each pair being combined with the topological distance separating the two central atoms. These so-called atom-pair molecular shingles are hashed, and the resulting set of hashes is MinHashed to form the MAP4 fingerprint. MAP4 significantly outperforms all other fingerprints on an extended benchmark that combines the Riniker and Landrum small molecule benchmark with a peptide benchmark recovering BLAST analogs from either scrambled or point mutation analogs. MAP4 furthermore produces well-organized chemical space tree-maps (TMAPs) for databases as diverse as DrugBank, ChEMBL, SwissProt and the Human Metabolome Database (HMBD), and differentiates between all metabolites in HMBD, over 70 % of which are indistinguishable from their nearest neighbor using substructure fingerprints. Conclusion: MAP4 is a new molecular fingerprint suitable for drugs, biomolecules, and the metabolome and can be adopted as a universal fingerprint to describe and search chemical space. The source code is available at <a href="https://github.com/reymond-group/map4">https://github.com/reymond-group/map4</a> and interactive MAP4 similarity search tools and TMAPs for various databases are accessible at <a href="http://map-search.gdb.tools/">http://map-search.gdb.tools/</a> and <a href="http://tm.gdb.tools/map4/">http://tm.gdb.tools/map4/</a>.<a href="http://tm.gdb.tools/map4/"></a>

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Developing degraders: principles and perspectives on design and chemical space

Abstract: Degraders (e.g. PROTACs, SNIPERs, degronimers etc.) are a new modality offering increasing potential both as tools for basic research and therapeutic development.

Cited by 123 publications

References 48 publications

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

PROTACs: great opportunities for academia and industry

One Molecular Fingerprint to Rule them All: Drugs, Biomolecules, and the Metabolome

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