Last week, the inaugural CACHE Symposium brought together leading experts in the field of computational chemistry and artificial intelligence to share their insights and experiences on advancing the field of computational hit finding and collaborating through open science.
Imagine being part of a world that shapes the future yet feeling invisible within it. This is the reality for women in STEM, who are nearly twice as likely as those in other fields to contemplate leaving their careers behind. The culprits? Overwhelming burnout, overlooked achievements, wage disparities, and a yearning for work that resonates on a deeper level.
To celebrate the International Day of Women and Girls in STEM earlier this year, I had the chance to interview a dynamic and global network of female scientists, who actively work to accelerate early drug discovery.
SGC's CIHR Award recipients. (L-R): Drs. Cheryl Arrowsmith, Matthieu Schapira, and Dalia Barsyte-Lovejoy.
The Canadian Institutes of Health Research (CIHR) has recently released the results of its Fall 2023 Project Grant funding competition. This competition aims to provide financial support to projects that will advance knowledge, research methodologies, patient care, and overall health outcomes.
The probe and control may be requested here.
| Probe | Negative control | |
 |  | |
TP-061 | TP-061N |
Bad response to refrigeration 2 (Brr2) is a 200 kDa protein and a member of DEXD/H-box helicase constituting a part of U5 snRNP. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step in the activation of spliceosome.
Takeda in collaboration with the University of Oxford and OICR has developed TP-061 as a potent inhibitor of Brr2. TP-061 exhibits IC50 of 21 nM in the ADP-Glo ATPase assay and 480 nM in the unwinding assay. Target binding is confirmed by SPR with Kd of 22 nM. The enantiomer, TP-061N, serves as an ideal negative control with IC50 of 84 mM in the ATPase assay.
TP-061 shows excellent selectivity over closely-related helicases, with no inhibition of eIF4A1, eIF4A3 and DHX29 up to 100 mM.
Additional selectivity over 300 kinases using in-house assay showed none with inhibition > 50% when tested at 1 mM.
Ito et. al. Discovery of spiro[indole-3,20-pyrrolidin]-2(1H)-one based inhibitors targeting Brr2, a core component of the U5 snRNP. Bioorg Med Chem., 2017, 25, 4753-4767, https://doi.org/10.1016/j.bmc.2017.07.017.
The probe and control may be requested here.
| Probe | Negative control | |
 |
|  |
SGC-UBD1031 |
| SGC-UBD1031N |
SGC in collaboration with Dr Mark Lautens’ at the University of Toronto’s Department of Chemistry has developed the first chemical probe SGC-UBD1031 for the ubiquitin binding domain (UBD) of USP16. SGC-UBD1031 has equipotent affinity to HDAC6 UBD and it is recommended to be used in parallel with SGC-UBD253.
SGC-UBD1031 binds potently to USP16 UBD with KD = 48 nM (SPR), and in cells it inhibits the USP16-ISG15 interaction with EC50 = 1.7 micromolar (nanoBRET).
SGC-UBD1031N is a closely related negative control with no activity in the nanoBRET assay up to 30 micromolar.
The SGC has dedicated the past twenty years to advancing scientific knowledge by freely distributing research tools, data, and technologies. With over half of human genes and their corresponding proteins still largely unexplored, and many diseases poorly understood, SGC focuses on increasing research into these understudied areas – but can’t do it alone! Our mission involves a global call to action, encouraging collaboration across continents and sectors to address critical challenges in drug discovery and biological research.
Left to right: John Moult, Judith Guenther, Okexandr Isayev
Can computational chemistry predict medicine-like molecules for any protein?
Maybe, but despite the ability of machine learning to identify such promising compounds, finding a reliable algorithm to select, design and rank these molecules remains a daunting challenge.
Frankfurt, February 26, 2024– The Structural Genomics Consortium (SGC) at Goethe University Frankfurt am Main has secured a significant €11.8 million in funding from the German Cancer Aid for the development of new, targeted cancer drugs, with a particular emphasis on rare tumor diseases.
The Structural Genomics Consortium at University College London (SGC-UCL) is led by Prof Matthew Todd. The group’s research is focused on the design and chemical synthesis of new small molecule protein binders towards medicines that improve human health.
The Structural Genomics Consortium at The Neuro (SGC Neuro) focuses on the “Dark Genome” targets, under-studied genes implicated in neurodegenerative disorders, and creating tools such as brain cells differentiated from genetically modified induced pluripotent stem cell lines and commercial antibody profiling through the