Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery

Pei, Haixiang; Peng, Yangrui; Zhao, Qi; Chen, Yi Hua

doi:10.1039/c9ra03423d

Cited by 51 publications

(36 citation statements)

References 81 publications

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“…Targeted protein degradation, in particular PROTACs, has attracted the attention of many academic institutions and pharmaceutical companies as a novel therapeutic approach in drug discovery [65,66]. This emerging technology has the ability to target the "undruggable" proteome, a limitation of traditional drugs [67,68]. These molecules are designed to enable ubiquitination of the target protein of interest, ultimately flagging it for degradation by the proteasome.…”

Section: Application Of Cross-coupling Reactions In Proteolysis Targementioning

confidence: 99%

Impact of Cross-Coupling Reactions in Drug Discovery and Development

2020

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Cross-coupling reactions have played a critical role enabling the rapid expansion of structure–activity relationships (SAR) during the drug discovery phase to identify a clinical candidate and facilitate subsequent drug development processes. The reliability and flexibility of this methodology have attracted great interest in the pharmaceutical industry, becoming one of the most used approaches from Lead Generation to Lead Optimization. In this mini-review, we present an overview of cross-coupling reaction applications to medicinal chemistry efforts, in particular the Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions as a remarkable resource for the generation of carbon–carbon and carbon–heteroatom bonds. To further appreciate the impact of this methodology, the authors discuss some recent examples of clinical candidates that utilize key cross-coupling reactions in their large-scale synthetic process. Looking into future opportunities, the authors highlight the versatility of the cross-coupling reactions towards new chemical modalities like DNA-encoded libraries (DELs), new generation of peptides and cyclopeptides, allosteric modulators, and proteolysis targeting chimera (PROTAC) approaches.

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Section: Application Of Cross-coupling Reactions In Proteolysis Targementioning

confidence: 99%

Impact of Cross-Coupling Reactions in Drug Discovery and Development

2020

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“…Among the representative H-PGDS selective inhibitors, HQL-79, 16 F092, 18 BSPT,19 TAS-204, 7 and TFC-007, TAS-204, and TFC-007 show high activity (with IC50 values of 23 and 83 nM, respectively, Figure 1a). [5][6][7][8] The binding mode between H-PGDS and F092 (and HQL-79) has been revealed by X-ray diffraction.…”

Section: Resultsmentioning

confidence: 99%

“…[12][13][14] A variety of PROTACs and SNIPERs have been developed for the treatment of cancer that targeted related proteins, such as transcriptional regulators, nuclear receptors, and protein kinases. 11,15,16 As a new mechanism of action for regulating the activity of H-PGDS, the development of degraders targeting the H-PGDS protein is an attractive approach for the treatment of chronic allergic diseases. In the present study, we developed the chimeric small molecule PROTAC(H-PGDS)-1, which had potent activity for the degradation of H-PGDS protein via the UPS and in the suppression of PGD2 production.…”

mentioning

confidence: 99%

Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

Yokoo

Shibata

Naganuma

et al. 2021

ACS Med. Chem. Lett.

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Although hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for treatment of a variety of diseases, including allergic diseases and Duchenne muscular dystrophy, no H-PGDS inhibitors have yet been approved for treatment of these diseases. Therefore, the development of novel agents having other mode of actions to modulate the activity of H-PGDS is required. In this study, a chimeric small molecule that degrades H-PGDS via the ubiquitin-proteasome system, PROTAC(H-PGDS)-1, was developed. PROTAC(H-PGDS)-1 is composed of two ligands, TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon). PROTAC(H-PGDS)-1 showed potent activity in the degradation of H-PGDS protein via the ubiquitin-proteasome system and in the suppression of prostaglandin D2 (PGD2) production. Notably, PROTAC(H-PGDS)-1 was slightly more effective in the suppression of PGD2 production than the known inhibitor, TFC-007. Thus, the H-PGDS degrader-PROTAC(H-PGDS)-1-is expected to be useful in biological research and clinical therapies. File list (2) download file view on ChemRxiv PROTAC(HPGDS)_201002_submitted.pdf (2.51 MiB) download file view on ChemRxiv SI_PROTAC(HPGDS)_201002_submitted.pdf (4.40 MiB)

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“…[184,185] PROTACS represents a conceptual shift away from the traditional drug discovery model of inhibiting biological function, and also offers opportunities to reduce therapeutic doses, overcome intracellular mechanisms of resistance and extend druggable chemical space. [186] An important consideration in the development of PROTACS, is the identification of E3 ligase capable of POI ubiquitylation. While to date only a small subset of E3 ligases have been exploited for PROTAC development, the human proteome contains over 600 different E3 ligases, meaning that there is significant scope for the identification of new E3 ligase recruiting ligands and the expansion of the PROTAC approach.…”

Section: Protacsmentioning

confidence: 99%

Into the Fray! A Beginner's Guide to Medicinal Chemistry

Veale

2021

ChemMedChem

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Modern medicinal chemistry is a complex, multidimensional discipline that operates at the interface of the chemical and biological sciences. The medicinal chemistry contribution to drug discovery is typically described in the context of the wellrecited linear progression of the drug discovery pipeline. However, compound optimization is idiosyncratic to each project, and clear definitions of hit and lead molecules and the subsequent progress along the pipeline becomes easily blurred. In addition, this description lacks insight into the entangled relationship between chemical and pharmacological properties, and thus provides limited guidance on how innovative medicinal chemistry strategies can be applied to solve optimization problems, regardless of the stage in the pipeline. Through discussion and illustrative examples, this article seeks to provide insights into the finesse of medicinal chemistry and the subtlety of balancing chemical properties pharmacology. In so doing, it aims to serve as an accessible and simple-to-digest guide for anyone who wishes to learn about the underlying principles of medicinal chemistry, in a context that has been decoupled from the pipeline description.

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Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery

Abstract: An overview of the latest developments in PROTAC technology and the possible directions of this approach is presented.

Cited by 51 publications

References 81 publications

Impact of Cross-Coupling Reactions in Drug Discovery and Development

Impact of Cross-Coupling Reactions in Drug Discovery and Development

Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

Into the Fray! A Beginner's Guide to Medicinal Chemistry

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