Thousands of targets are considered “undruggable” because so far, it’s been impossible to find drugs to inhibit their function. Instead of trying to inhibit these targets, it may be easier to degrade them. To do this, researchers develop small molecules such as PROTACs (Proteolysis Targeting Chimeras) and molecular glues that tag a target for destruction by the proteasome, effectively removing them from circulation.
Take a look at how NanoTemper tools are used to characterize molecular interactions in binary and ternary complexes during the development of therapeutic PROTACs and molecular glues.
Find the right tools to characterize binary and ternary complexes
Researchers developing PROTACs and other targeting chimeras, like RIBOTACs used in RNA targeted degradation, have a hard time finding a biophysical method that efficiently characterizes binary and ternary molecular interactions. They look for a method that measures binding affinities in the pM to mM range, in solution under controlled equilibrium conditions, and is able to screen for both PROTACs and ligases.
Learn how Dianthus is used to measure ternary interactions when screening PROTAC candidates
Leveraging targeted protein degradation to fight cancer
Each of the parts that make up a PROTAC — E3 ligase recognition motif, the ligand for the targeted protein, and a linker — plays a role in their affinity and specificity. So it’s essential to find one tool that can characterize these attributes during development. Learn how these groups used MST to evaluate the affinity and specificity of their PROTACs to trigger targeted protein degradation in the fight against cancer.
PROTAC-induced degradation of CREPT inhibits tumor growth
Pancreatic cancer is among the hardest to treat and the deadliest of cancers. CREPT is an oncoprotein involved in the progression of pancreatic cancer, but targeting it with traditional chemotherapeutic drugs can lead to off-target effects and negative host responses. Learn how this group designed a PROTAC that effectively targets CREPT and suppresses pancreatic tumor growth in a mouse model. MST helped determine the affinity of the unique PROTAC for CREPT.
Improved PROTACs specificity using peptides as linkers
PROTACs offer great new potential in preclinical applications. However, their development suffers from the same problems seen in the development of small molecule drugs, like toxicity and lack of specificity. Using peptides as the PROTAC linker offers scientists the possibility to increase specificity and also reduce off-target effects. Learn more about how peptide-based PROTAC degraders work, and the advantages MST offers for studying their interactions.
Targeting RNA degradation to treat diseases
Many microRNAs (miRNAs) implicated in diseases are also notoriously difficult to target with traditional small molecule drug approaches. Inspired by how PROTACs are paving the way to find drugs for challenging targets, scientists are developing RIBOTACs — small molecules that bind the disease-causing miRNAs and recruit RNase for degradation. See how these teams used the promise of targeted degradation to improve the affinity of their RIBOTACs using MST during development and selection.
A specific way to target disease-associated miRNAs for degradation
Certain microRNAs can be overexpressed in diseases such as cancer, making them a desired target for therapeutics. The challenge is to design small molecules with high affinity for RNA that do not cross-react with DNA. In this study, a group targeted the degradation of a cancer-associated miRNA by combining RNA-targeting small molecules with polyadenylate linkers to specifically recruit RNase L. Learn how they used MST technology as a guide to improve the affinity for their target.
Successful targeted degradation of SARS-CoV-2 RNA
The COVID-19 pandemic revealed the need to rapidly develop therapeutics that can prevent or reduce viral infection. This group was able to develop a small molecule capable of targeting the SARS-CoV-2 RNA genome. When that small molecule is linked to a RIBOTAC, RNase L is recruited and degrades the viral genome. Read how MST assisted in small molecule selection and RIBOTAC development.