Identification of new, reliable targets is an important process in modern drug development. Chemical genetics is a powerful way to discover new targets. Unlike traditional target-based screening, which relies on predefined and sometimes poorly validated targets, Creative Biolabs' chemogenetic phenotypic screening detects the entire molecular signaling pathway for the most sensitive drug molecules in an efficient and unbiased way to help our customers refine their drug development programs.
In the past decade, the number of new molecular entity drugs approved each year has continued to decline. At the same time, the discovery and validation of new targets associated with disease remain low, and many disease-related targets and pathways remain “undruggable”. It can be argued that the reduction in innovative medicines is mainly due to the exhaustion of proven and easy-to-handle objectives, and it is clear that traditional medicines and target discovery methods are no longer effective. In order to maintain a healthy pipeline of novel validated targets for drug discovery, biopharmaceutical companies have begun to establish a drug target recognition platform based on chemical genetics. The platform can systematically assess the effects of genetic variation on drug activity and is now more widely used in human cell lines.
Fig.1 Gene-dosage perturbations reveal drug targets.
The drug target screening based on gene expression library is mainly based on the following theory: when the target gene is down-regulated, the response of the cell to the drug will be more intense, on the contrary, the overexpression of the target gene will increase the tolerance of cells to drugs. For most diploid organisms, a library of heterozygous deletion mutants can be used to reduce the dose of essential genes. Such screens, dubbed as HaploInsufficiency Profiling (HIP), were the first to be used to successfully map drug cellular targets in yeast. For the haploid genetic system of bacteria, the technique for increasing the level of gene expression is very simple, so it is usually used for overexpression to screen drug targets.
With the advancement of CRISPR technology in recent years, CRISPRi libraries of essential genes have been constructed in different bacteria and used to identify drug targets. Compared to overexpression approaches, knockdown libraries of essential genes have the advantage of being better tailored for capturing the cellular target when this is part of a protein complex. However, for most current drug target screening programs, knockout and overexpression methods may incorrectly screen for genes that produce resistance. Creative Biolabs overcomes these deficiencies by combining results of increased and decreased gene dosage and by more generally titrating gene dosage, or by checking dynamic responses after modulating the levels of essential genes. Currently, we have begun to use chemical genetics to screen drug targets in the human genome on a large scale.
If you have any questions about our drug discovery service, you can contact us by email or send us an inquiry to find a complete solution.
For Research Use Only.
