The era of high-quality chemical probes

Licciardello, Marco P.; Workman, Paul

doi:10.1039/d2md00291d

Cited by 35 publications

(18 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, ART558 has been added to the chemical probes listed in the Chemical Probe Portal () and is currently in the process of review by the Scientific Expert Review Panel (SERP) to assign it a rating. Additional in vitro / in vivo characterization of ART558 will certainly favor its qualification as a high-quality chemical probe . As such, it will represent an important asset in the efforts to expand the knowledge on the biology of POLθ.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer Therapy

et al. 2023

View full text Add to dashboard Cite

Synthetic lethality (SL) is an innovative strategy in targeted anticancer therapy that exploits tumor genetic vulnerabilities. This topic has come to the forefront in recent years, as witnessed by the increased number of publications since 2007. The first proof of concept for the effectiveness of SL was provided by the approval of poly(ADP-ribose)polymerase inhibitors, which exploit a SL interaction in BRCA-deficient cells, although their use is limited by resistance. Searching for additional SL interactions involving BRCA mutations, the DNA polymerase theta (POLθ) emerged as an exciting target. This review summarizes, for the first time, the POLθ polymerase and helicase inhibitors reported to date. Compounds are described focusing on chemical structure and biological activity. With the aim to enable further drug discovery efforts in interrogating POLθ as a target, we propose a plausible pharmacophore model for POLθ-pol inhibitors and provide a structural analysis of the known POLθ ligand binding sites.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Additional in vitro / in vivo characterization of ART558 will certainly favor its qualification as a high-quality chemical probe. 137 As such, it will represent an important asset in the efforts to expand the knowledge on the biology of POLθ.…”

Section: Discussionmentioning

confidence: 99%

Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer Therapy

et al. 2023

View full text Add to dashboard Cite

show abstract

“…The ability of chemical probes to rapidly perturb biological function makes them a complementary approach to nucleic acid‐based approaches such as RNAi and CRISPR [2] . Despite the tremendous promise of chemical tools, small‐molecule probes are currently available for less than 4 % of the human proteome [3,4] . Historically, the discovery of chemical probes has primarily followed a target‐centric approach, and often relies on knowing an enzymatic function (e.g., kinase, protease) in order to screen for inhibitors.…”

Section: Figurementioning

confidence: 99%

“…[2] Despite the tremendous promise of chemical tools, small-molecule probes are currently available for less than 4 % of the human proteome. [3,4] Historically, the discovery of chemical probes has primarily followed a target-centric approach, and often relies on knowing an enzymatic function (e.g., kinase, protease) in order to screen for inhibitors. A complementary approach involves phenotypic screening, which allows for identification of unexpected pharmacology but is often impeded by the difficulty of elucidating the target and mechanism of action of the identified compounds.…”

mentioning

confidence: 99%

Proteomics‐Based Discovery of First‐in‐Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2)

Ji,

Byun,

et al. 2023

Angew Chem Int Ed

View full text Add to dashboard Cite

Chemical probes are essential tools for understanding biological systems and for credentialing potential biomedical targets. Programmed cell death 2 (PDCD2) is a member of the B‐cell lymphoma 2 (Bcl‐2) family of proteins, which are critical regulators of apoptosis. Here we report the discovery and characterization of 10e, a first‐in‐class small molecule degrader of PDCD2. We discovered PDCD2 degrader by serendipity using a chemical proteomics approach in contrast to the conventional approach for making bivalent degraders starting from a known binding ligand targeting the protein of interest. Using 10e as a pharmacological probe, we demonstrate that PDCD2 functions as a critical regulator of cell growth by modulating the progression of the cell cycle in T lymphoblasts. Our work provides a useful pharmacological probe for investigating PDCD2 function and highlights using chemical proteomics to discover selective small molecule degraders of unanticipated targets.

show abstract

“…The necessity of chemical probes for mechanistic and target validation research 1 – 10 has led to a steadily growing number of high-quality chemical probes 10 . Every chemical probe must satisfy the minimal fundamental criteria, known as fitness factors: namely potency, selectivity, and cellular activity 1 , 9 .…”

Section: Introductionmentioning

confidence: 99%

Systematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research

et al. 2023

View full text Add to dashboard Cite

Chemical probes have reached a prominent role in biomedical research, but their impact is governed by experimental design. To gain insight into the use of chemical probes, we conducted a systematic review of 662 publications, understood here as primary research articles, employing eight different chemical probes in cell-based research. We summarised (i) concentration(s) at which chemical probes were used in cell-based assays, (ii) inclusion of structurally matched target-inactive control compounds and (iii) orthogonal chemical probes. Here, we show that only 4% of analysed eligible publications used chemical probes within the recommended concentration range and included inactive compounds as well as orthogonal chemical probes. These findings indicate that the best practice with chemical probes is yet to be implemented in biomedical research. To achieve this, we propose ‘the rule of two’: At least two chemical probes (either orthogonal target-engaging probes, and/or a pair of a chemical probe and matched target-inactive compound) to be employed at recommended concentrations in every study.

show abstract

The era of high-quality chemical probes

Abstract: Small-molecule chemical probes are among the most important tools to study the function of proteins in cells and organisms. Regrettably, the use of weak and non-selective small molecules has generated...

Cited by 35 publications

References 109 publications

Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer Therapy

Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer Therapy

Proteomics‐Based Discovery of First‐in‐Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2)

Systematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research

Contact Info

Product

Resources

About