New technologies and approaches in drug small molecule development

Release time: 2022-01-20

Screening is the most important basic method in the development of modern small molecule drugs. To conduct screening, we must first discover the target of a drug that is indicative of a disease, such as receptors, enzymes, transporters or ion channels. , signal proteins, structural proteins, tubulin, actin, etc.; secondly, there must be a small molecule library (Library), which provides a sufficient number of molecules for screening, and finds one or more target compounds from the corresponding library that meet the requirements. (Hit), through layer-by-layer structure optimization, lead compounds (Lead) and candidate compounds (Candidate) are obtained, and their safety and effectiveness are fully verified through systematic clinical trials.

With the rapid development of molecular biology and structural biology, small molecule drug discovery has entered the era of target-based drug design. Researchers can perform high-throughput screening based on a certain target to obtain the composite crystal structure of small molecules and target proteins, and rationally optimize them with the aid of computers, which makes the development of drugs clear and clear. However, High Throughput Screening (HTS), Virtual Screening (Virtual Screening), Structure-based Drug Design (SBDD) and Fragment-based Drug Discovery (FBDD) have gradually become small Common technologies for molecular drug discovery and development, these technologies have achieved great success and are still constantly enriched and developed.

At the same time, there are many new technologies and methods in the field of small molecules, such as two protein degradation therapies, PROTAC and molecular glue. Among them, PROTAC technology is undoubtedly one of the most active small molecule research and development technologies. On July 20, 2021, a heavyweight Perspective: The PROTACtable genome was published in the journal Nature ReviewsDrug Discovery. It mainly explained proteolytic targeting chimeras (PROTACs), and proposed a system to evaluate the PROTACability of protein targets. (PROTACtability) method and 1,067 potential PROTAC targets. It is expected that by the end of 2021, at least 15 protein degradation therapies under investigation will enter the clinical trial stage, including at least 10 heterobifunctional protein degraders (PROTAC, BiDAC, etc.) and 5 molecular glue degraders.

In addition, the application of new technologies such as DNA-encoded compound library (DEL) technology, gene encoding technology and AI technology will play an important role in the development of small molecule drugs, improving the efficiency, success rate and competitiveness of small molecule drug development.

PROTAC (Proteolysis-Targeting Chimeras) is a drug development technology that utilizes the Ubiquitin-Proteasome System (UPS) to degrade target proteins. Raymond, Deshaies and others first proposed the concept of PROTAC in 2001, and successfully designed and synthesized the first batch of PROTAC bifunctional molecules for the degradation of methionyl aminopeptidase 2.

Structurally, PROTAC consists of three parts: the E3 ubiquitin ligase ligand, the target protein ligand, and the "Linker" that connects the two ligands. In patients, one end of the PROTAC molecule binds to a protein of interest (POI, protein of interest), and the other end binds to E3 ligase to form a ternary complex. The recruited E3 ligase then mediates the transfer of ubiquitin from the E2 enzyme to the POI. After the dissociation of the ternary complex, the ubiquitinated POI is degraded by the proteasome, and the PROTAC molecule can continue to bind the next POI.

According to the Clarivate Analytics database, as of August 30, 2021, a total of 16 PROTAC drugs have entered the clinical stage, including 3 in clinical phase 1 and 3 in clinical phase 2, with targets including AR, ER, BCL-XL, IRAK4, STAT3, BTK, TRK and BRD9 etc.

Molecular gel degraders are a class of small molecules that can induce the interaction between E3 ubiquitin ligase substrate receptors and target proteins, resulting in the degradation of target proteins. Thalidomide-based anticancer drugs are a typical example of molecular glues that redirect the E3 ubiquitin ligase CRBN to polyubiquitinate transcription factors IKZF1 and IKZF3 for degradation by the proteasome. The concept of "molecular glue" was first proposed in the early 1990s. The immunosuppressants cyclosporine A (CsA) and FK506 were the first molecular glues. There are 5 molecules currently in the clinical research stage, and the targets include IKZF2, IKZF1/3, GSPT1 and so on.