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Researchers now have access to an enhanced resource for studying protein function and developing innovative therapies as the Chemical Probes Portal announces it has reached the milestone of covering over 600 protein targets. This milestone highlights the Portal’s key role in supporting the advancement of basic biological research, chemical biology and drug discovery, offering robust recommendations of high-quality inhibitors and other modulators to explore diverse biological pathways. A total of 601 protein targets now covered, the majority being addressed by three-star or four-star chemical probes, reflecting their suitability for investigating specific proteins in cellular or in vivo systems with high confidence. These targets span a broad spectrum of target classes, including kinases, epigenetic regulators, GPCRs, and emerging classes such as RNA-binding proteins and E3 ligases.

New protein targets covered

New targets addressed include the dCTP pyrophosphatase 1 (DCTPP1), which is involved in nucleotide metabolism and plays pro- and anti-cancer roles by modulating tumour growth and drug resistance as well as being a marker for immunotherapy. Thus, further research on DCTPP1 will be enabled by the chemical probe ZINC4511851. Microtubule associated serine/threonine kinase like (MASTL), which is involved in cellular proliferation by regulating mitosis M phase and is associated with cancer progression, is addressed by the novel first-in-class probe MASTL-IN-1 which may enable development of new therapeutics for mitotic checkpoints. We also now also have on the Portal the HCN1 inhibitor RO-275. HCN1 is an ion channel protein implicated in different cognitive deficits and was previously considered to be undruggable. Together with the availability of several good quality compounds for neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, and new additions of compounds for targets implicated in cardiovascular diseases and migraine, the Portal will continue to expand its target space portfolio. Our increasingly broad coverage of targets like these will help the biology community to choose the best compounds for robust and reproducible research.

Expanding Targeted Protein Degradation

The latest additions to the Portal highlight the growing prominence of targeted protein degradation as a potential transformative approach in drug discovery. Newly included probes include those that engage both established and novel E3 ligases, alongside PROTACs and molecular glues for degrading challenging targets. This expansion provides researchers with reliable resources for exploring targeted protein degradation in biological and therapeutic research.

Addressing Gaps in Chemical Biology

While celebrating this achievement, the Portal continues to address unmet needs in the field. More than 250 ‘Unsuitables’ compounds are included on the Portal, helping users recognize the limitations of outdated or nonspecific inhibitors and guiding them toward better alternatives. For instance, compounds like quercetin, still often cited, are flagged because of poor selectivity and high off-target activity. Instead, the Portal recommends more suitable alternatives for reliable experimental outcomes. The Portal provides important advice on recommended concentration ranges and often also on inactive and orthogonal active control compounds, as recommended in our recent commentary Probing cancer with small-molecule tools-Progress and challenges

A Milestone for the Community

“Exceeding 600 protein targets covered is a significant achievement for the Chemical Probes Portal and the broader scientific community,” says Professor Paul Workman, Director of the Portal and Harrap Professor of Pharmacology and Therapeutics at the Institute of Cancer Research, London. “This accomplishment reflects the dedication of our 250-member Scientific Expert Review Panel and the contributions of researchers worldwide who submit their compounds for review. But our work is far from over. We still need high-quality probes for the large number of unexplored proteins in the human proteome, and we encourage the community to collaborate with us in this endeavour. The Chemical Probes Portal’s commitment to best practice is integral to its success. Researchers are urged to use the Portal’s guidelines, as highlighted in our recent publication on developing, selecting and using chemical probes. By leveraging high-quality tools reviewed on the Portal, researchers can deepen our understanding of protein function and accelerate the development of more effective therapeutics.”

Looking Ahead: Target 2035

In alignment with the Target 2035 initiative, the Portal aims to support the discovery and availability of chemical probes for every protein in the human genome by year 2035. This ambitious goal underscores the need for continued innovation and collaboration. Researchers are encouraged to submit new compounds, join the Scientific Expert Review Panel, and engage with the Target 2035 initiative to propel the field forward.

Chemical Probes Portal Reaches 600+ Targets