New Technologies and Methods in Small Molecule Drug Development

Compared with biological drugs, small molecule drugs have greater advantages in R&D cost and process maturity, and they are still the main battlefield for drug research and development. According to statistics, the FDA has approved 53 new drugs in 2020, including 40 chemical drugs and 13 biological drugs.

Screening is the most important basic method in the research and development of small molecule drugs. For screening, we must first discover the target of a disease, such as receptors, enzymes, transporters, ion channels, signal protein, structural protein, tubulin, actin, etc.; secondly, there is a small molecule library, which provides enough molecules to screen, and find one or more compounds that meet the requirements from the corresponding library, after structure optimization, lead compound and candidate compound are obtained, and then the safety and effectiveness are fully verified through 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 target to obtain a composite crystal structure of small molecules and target proteins, and perform optimization with the aid of computers, making drug development clear. High throughput screening (HTS), virtual screening, structure-based drug design (SBDD), and fragment-based drug design (FBDD) have gradually become common technologies for small molecule drug research. These technologies have achieved great success and are still in continuous development.

At the same time, many new technologies have emerged in the field of small molecules, such as PROTAC and molecular glue, two protein degradation therapies. Among them, PROTAC technology is undoubtedly one of the most active research and development technologies. On July 20, 2021, Nature Reviews Drug Discovery published an important perspective: The PROTACtable genome. It mainly explained proteolytically targeted chimeras (PROTACs), and proposed a method to system evaluation PROTACtability and 1,067 potential PROTAC targets. It is expected that by the end of 2021, at least 15 protein degradation therapies under development will enter the clinical trial stage, including at least 10 heterobifunctional protein degradation agents (PROTAC, BiDAC, etc.) and 5 molecular gel degradation agents.

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

PROTAC

PROTAC (Proteolysis-Targeting Chimeras) is a drug development technology that uses 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.

PROTAC includes three parts: E3 ubiquitin ligase ligand, target protein ligand, and linker that connects these two ligands. In the patient’s body, one end of the PROTAC molecule binds to the protein of interest (POI), and the other end binds to the E3 ligase to form a ternary complex. Then, the recruited E3 ligase mediates the transfer of ubiquitin from E2 enzyme to POI. After the ternary complex dissociates, the ubiquitinated POI is degraded by the proteasome, and the PROTAC molecule can continue to bind to the next POI.

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. The targets include AR, ER, BCL-XL, IRAK4, STAT3, BTK, TRK And BRD9 and so on.

Molecular Glues Technology

Molecular glue degradation agents are small molecules that can induce the interaction between the E3 ubiquitin ligase substrate receptor and the target protein, thereby leading to the degradation of the target protein. Thalidomide, anticancer drugs, are a typical representative of molecular glues. Such drugs can redirect the E3 ubiquitin ligase CRBN, so that the transcription factors IKZF1 and IKZF3 are polyubiquitinated and degraded by the proteasome. The concept of “molecular glue” was first proposed in the early 1990s. The immunosuppressant cyclosporin A (CsA) and FK506 are the first molecular glues. There are currently 5 molecules in the clinical cltrial stage, the targets include IKZF2, IKZF1/3, GSPT1, etc.

DNA-Encoded Library Technology (DEL)

DNA-encoded library technology (DELT) refers to the synthesis of a huge-scale compound library by combining a large number of chemical molecular building blocks. Each building block corresponds to a unique DNA code, similar to a barcode. Correspondingly, a compound synthesized from multiple building blocks also has a unique barcode, which is generated by the combination of the codes of all building blocks in the compound. According to this principle, DEL technology can be applied to database construction and drug screening. DEL technology is one of the emerging small-molecule drug screening technologies in recent years. Since it was proposed in 1992, the technology has gradually moved to the industrial world and has been favored by major multinational pharmaceutical companies. DEL technology has also become one of the main method for compound screening due to its large library capacity and fast screening speed. The construction strategies of DNA coding compound library mainly include: DNA recording synthesis method, DNA template method, DNA routing synthesis method, ESAC synthesis method and so on.

Gene Editing Technology

Gene editing technology is a classic and commonly used molecular biology technology, which is widely used in drug development, gene therapy, basic research, and diagnostic technology development. The core of gene editing technology is to modify genomic DNA through programmed artificial nucleases. For the development of small molecule drugs, gene editing can solve pre-clinical evaluation systems, new target discovery, and drug resistance issues through gene knock-in, gene knock-out, base switching.

Gene editing technology can provide a preclinical screening platform for small molecule drug research and development. It can edit target genes at the genome level, and can highly simulate disease mechanisms and progress, greatly simplifying the modeling process and shortening the modeling cycle. Gene editing technology provides more practical cell and animal models for the development of small molecule drugs. Examples of this type are widely used in metabolic diseases and the central nervous system. In addition, gene editing technology can be used to screen drug targets on a large scale.

Artificial Intelligence (AI) Technology

In recent years, with the continuous maturity of artificial intelligence (AI) technology, artificial intelligence has been found in the target site, the discovery of hit compounds and lead compounds, the design of drug molecular synthesis routes, the establishment of disease models, and the discovery of new indications. Helping the research and development of new drugs in many other aspects will greatly improve the research and development efficiency of new drugs.