Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766)

Chessum, N.; Sharp, Swee Y.; Caldwell, John; Pasqua, Adele E.; Wilding, Birgit; Colombano, Giampiero; Collins, Ian; Özer, Buğra; Richards, Meirion; Rowlands, Martin; Stubbs, Mark; Burke, Rosemary; McAndrew, P.C.; Clarke, Paul A.; Workman, Paul; Cheeseman, Matthew D.; Jones, Keith

doi:10.1021/acs.jmedchem.7b01406

Cited by 82 publications

(79 citation statements)

References 72 publications

(124 reference statements)

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“…[16,17] Indeed, IMiDs have been widely used as E3 recruiting elements to enable the degradation of aw ide variety of targets. [18][19][20][21][22][23][24][25] Intrigued by the "molecular glue" mechanism of these compounds, we sought to explore the structure-degradation relationships (SDR) of IMiD analogues with an aim to elucidate the requirements for neo-substrater ecruitmenta nd the development of high-affinity recruiting elementsf or use in PROTACs. Previous SAR studies have provenc hallengingd ue to both time-consuming synthesis and insufficient knowledge surrounding the mechanism of action prior to 2014.…”

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confidence: 99%

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

et al. 2018

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The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure-activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure-degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.

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confidence: 99%

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

et al. 2018

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“…The knockdown of pirin via siRNA could suppress cancer cell migration and proliferation. 298,299 Jones and coworkers reported a high affinity pirin chemical probe CCT251236 via a phenotypic screen to develop pirintargeting PROTACs 300 (Fig. 34).…”

Section: Pirinmentioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

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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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“…developed degradation molecules, called CLIPTACs, which self‐assembled in live cells following inverse electron demand Diels–Alder (iEDDA) cycloaddition between tetrazine (Tz) and trans ‐cyclo‐octene (TCO) motifs present on the cognate recruiting partners (Figure D) . The benefit of this CLIPTAC technology is to circumvent the potentially poor permeability of large bifunctional PROTAC molecules . A covalent CLIPTAC ( 16 ), resulting from the intracellular IEDDA reaction between a TCO‐tagged electrophilic kinase binder and a Tz‐thalidomide derivative (Figure B), was able to degrade ERK1/2 in A375 and HCT116 cell lines.…”

Section: Covalent Inducers Of Protein Degradationmentioning

confidence: 99%