Quantitative Chemical Biology

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A Small Molecule that Targets an RNA Repeat Expansion

Toxic structured RNAs cause many different diseases. For example, myotonic dystrophy type 1 (DM1) is caused by r(CUG) repeat expansion [r(CUG) exp ] harboured in the 3’ untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. DM1 is one of the most common forms of adult-onset muscular dystrophy, affecting approximately 1 in 8,000 people. r(CUG) exp binds to and sequesters various proteins, particularly the pre-mRNA splicing regulator muscleblind-like 1 (MBNL1), which limits the number of MBNL1 available to regulate pre-mRNA splicing and causes system-wide defects. Recently, r(CUG) exp was confirmed to cause another disease called Fuchs endothelial corneal dystrophy (FECD), in which the repeat expansion resides in intron 3 of the transcription factor 4 (TCF4) pre-mRNA. FECD is a dominantly inherited corneal disease that affects as many as 5% of Caucasian males and results in vision impairment. Similar to DM1, r(CUG) exp also sequesters MBNL1 in FECD, causi

First PROTAC Degradation of Mulit-Pass Transmembrane Protein

Cancer cells exploit proteins involved in energy metabolism to maintain a steady supply of building blocks necessary for increased proliferation. Many transporters play a role in the process of shuttling water, nutrients, ions, and various metabolic products across the cell membrane, including the solute carrier (SLC) group of proteins. The SLC protein group consists of more than 400 proteins organized into more than 50 families. For example, the SLC9 family is involved in intracellular pH homeostasis, with increased SL9 activity resulting in an elevated intracellular pH and cytosolic alkalinization in cancer. Currently there 12 FDA approved drugs targeting SLC proteins for conditions ranging from hypertension to depression, but recent studies suggest SLC proteins may be attractive targets for cancer drug development. With this end goal, Bensimon et al., aimed to investigate if multi-pass transmembrane proteins like SLCs can be chemically degraded. To first explore this aim, th

Identification of a covalent BFL-1 inhibitor

Evading apoptosis is one of hallmarks of cancer and highly associated with chemotherapy resistance. The BCL-2 family of proteins govern both intrinsic apoptosis and are frequently dysregulated in various cancers. So far, small molecules have been developed to effectively block BCL-2, BCL-XL, and MCL-1. A selective BCL-2 inhibitor, Venetoclax, is the first FDA approved for the treatment of CLL, and other BCL-XL and MCL-1 inhibitors are currently in clinical trials. Among six anti-apoptotic BCL-2 family proteins, BFL-1 is considered undruggable, being the least studied, however, a growing body of evidence suggests its value as a therapeutic target acting as resistant factors to other BCL-2 family proteins inhibitors in lymphoma and to MAPK inhibitors in melanoma. Thus, selective BFL-1 inhibitors held clinical promise. Recently, a small molecular covalent BFL-1 inhibitor targeting cysteine has been described in a paper in “Cell Chemical Biology”. The unique cysteine55 in the BH3

Analogues of Chrysomycin A as Leads for Drug-Resistant Tuberculosis

Tuberculosis (TB) remains a major cause of death globally, primarily in underdeveloped countries, and imposes approximately 12 billion USD annually in economic burdens to society. Furthermore, multi-drug-resistant (MDR) and extreme-drug-resistant (XTR) TB are widespread illnesses that cause up to 250,000 deaths annually, thus emphasizing the need for drugs with new mechanisms of action. Recently, the natural product chrysomycin A was identified as having potent anti-TB activity in a high-throughput screen (MIC = 0.4 µg/mL against MDR-TB). Chrysomycin A is a rare C-aryl glycoside whose yields via fermentation from its natural source are insufferably low. To provide sufficient materials for biological testing, the group of Xiaoguang Lei devised a total synthesis route to chrysomycin A ( 1 ), its natural congeners polycarcin V ( 8 ) and gilvocarcin V ( 10 , Figure 1 ), and 33 new analogues. The preparation of a late-stage intermediate that is amenable to diversific

Loss of Elf5 Wakes up “A Good Friend” of Triple-Negative Breast Cancer

Triple-negative breast cancers (TNBCs), defined by lack of expression of estrogen receptor, progesterone receptor and HER2, account for 12-17% of breast cancers and are clinically perceived as a discrete breast cancer subgroup. Despite an aggressive approach in the management of TNBCs with current therapy, the recurrence and 5-year survival rates for TNBC stand at 50% and 37%, respectively. Therefore, for doctors and researchers, there is tense interest in finding new medications that can treat this kind of breast cancer more efficiently. E74-like transcription factor (Elf5) functions as a suppressor of epithelial-to-mesenchymal transition (EMT), a characteristic that imparts the tumor’s invasive and metastatic properties. Snahlata Singh et al. found that the loss of Elf5 increases tumor burden, growth and metastasis by activating intrinsic interferon- γ (IFN-γ), a cytokine that is both anti- and pro-tumorigenic. Mechanistically, they discovered that Elf5 inhibits IFN-γ signalli

Grafting Alkyne Handles on Cysteines

One of the most common ways to study biomolecules is to label specific amino acids, mostly cysteine, with chemical handles for further modification. Azide-alkyne click reaction is a very popular strategy due to its high reactivity and reaction rate. Therefore, numerous reagents have been developed to specifically label proteins with terminal alkynes, including iodoacetamide alkynes and maleimide derivatives. However, limitations like insufficient selectivity and low stability remain as long-lasting concerns. To address these problems, one common strategy is introducing a linker between the targeting residue and the alkyne moiety , which potentially brings in unwanted structural changes. A reagent that can introduce small-sized terminal alkyne with one step under mild conditions is in demand. Scheme 1 . Cysteine-labeling study in this work In this study, the Waser group presented a series of reagents that selectively ethynylate cysteine in a one-pot manner ( Scheme 1 ). The