2020s Top Probes
Ten outstanding compounds that joined the Portal in 2020.
2020 was the first year of visible activity on the Chemical Probes Portal since 2017, with 115 probes added and over 500 compounds now included on the Portal. To celebrate, we’re highlighting ten of the best probes added to the Portal and evaluated by our Scientific Advisory Board in 2020. These probes are selective, potent, cell-active molecules that are rated four stars for use in cells and target new proteins or have new mechanisms of action. They include probes for previously ‘undruggable’ cancer targets, compounds that target GPCRs, epigenetic modulators and PROTACs.
Targeting cancer
KRAS inhibitors, AMG-510 and MRTX849
KRAS was thought to be an undruggable target due to its high affinity for the natural substrate. Despite its key role in many cancer types, no inhibitor was available. That changed with the development of two small molecules, AMG-510 and MRTX849, which target the cancer-driving mutant, KRAS G12C, and bind covalently to the cysteine at position 12. KRAS G12C mutations can be found in non-small cell lung cancer, as well as pancreatic cancer and other solid tumors and so these inhibitors show great promise to improve the lives of cancer patients in the near future.
www.chemicalprobes.org/AMG-510
www.chemicalprobes.org/MRTX849
AB680
AB680 reversibly inhibits the ecto-nuclotidase CD73, which converts AMP to adenosine in the tumour microenvironment, with immunosuppressive effects. With extensive structure-activity relationship (SAR) data, AB680 is a highly potent (Ki 5 pM), reversible and selective CD73 inhibitor. Targeting CD73 has promise in cancer treatment in combination with immunotherapies.
Luminespib, HSP90 inhibitor
Luminespib selectively inhibits HSP90, binding to the N-terminal nucleotide binding site with an in vitro IC50 of 7.8nM for the HSP90α subunit and 21 nM for HSP90β. HSP90, a protein-folding chaperone, is linked to several cancers. In 2020, HSP90 and Luminespib were investigated in relation to Covid-19, for the role of HSP90 in the folding of unstable virus proteins. Clinical trials of HSP90 inhibitors are ongoing.
www.chemicalprobes.org/luminespib
Investigating epigenetics
NUDIX hydrolases
Probes for two NUDIX hydrolases joined the Portal in 2020. TH5427 selectively inhibits NUDT5 (690 times selective for NUDT5 over other NUDIX hydrolases showing an in vitro potency [IC50] of 29 nM). TH5427 has a role in ADP-ribose metabolism within cells, and the generation of ATP in the nucleus. NUDT5 has been linked to breast cancer and TH5427 is a valuable tool for exploring the role of NUDT5 in this disease.
TH1760 is the first selective NUDT15 inhibitor. TH1760 has nanomolar potency, is selective for NUDT15 over other closely related proteins and has been extensively characterized in vitro and in cells. NUDT15 has a sanitation function, removing modified nucleotides from cells, particularly 6-thio-(d)GTP. Leukemia treatments aim to increase the concentration of this altered nucleotide in the cell, which is incorporated into DNA, resulting in cell death. Inhibiting NUDT15 could therefore play a role in sensitising cells to these therapies.
Activating GPCRs
25CN-NBOH, serotonin receptor, HTR2A, agonist
Complementing a collection of selective antagonists for serotonin receptors, 25CN-NBOH selectively activates the serotonin receptor HTR2A, and is one of the most selective agonists for this important G-protein coupled receptor (GPCR), with 100-fold selectivity for HTR2A over HTR2C and 46-fold over HRT2B in cells. 25CN-NBOH shows a different binding mode compared to LSD and therefore represents a valuable tool to study HTR2A activation. This probe has been rated four stars by the Portal and is recommended for use in cells and mouse models.
www.chemicalprobes.org/25CN-NBOH/
UCSF4226 and UCSF7447, Melatonin receptor probes
UCSF4226 and UCSF7447 are two new tools to study GPCRs that respond to melatonin signalling, MT1 (MTNR1A) and MT2 (MTNR1B), and could be used alongside each other to investigate the MT receptors. Both are potent molecules, and each has over 50-fold selectivity for its human target protein over the other melatonin receptor.
UCSF4226 is a selective agonist for MTNR1B, mimicking the presence of melatonin. UCSF7447 is an inverse agonist for MTNR1A, antagonising the effect of the receptor agonist.