Small Molecule Drug Target Proteins: From Target Evaluation to the Core Support of Drug Innovation

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This article systematically elaborates on the classification methods of target-disease association types, integration strategies for target information sources, and research trends in existing oncology drug targets, centering on the evaluation strategies and drug development applications of small-molecule drug target proteins. It explores the core value of disease-drug mechanism information networks in target discovery.

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Small Molecule Drug Target Proteins: Core Support from Target Evaluation to Drug Innovation

Summary
This article systematically elaborates on the evaluation strategies and drug development applications of small molecule drug target proteins, including the classification methods of target-disease associations, integration strategies for target information sources, and research trends in existing oncology drug targets. It explores the core value of disease-drug mechanism information networks in target discovery.

I. Classification and Evaluation Strategies for Target-Disease Associations.

The current target evaluation process starts with diseases, acquiring drug information at different stages to assess corresponding targets and guide R&D project decisions. In this process, clarifying the type of target-disease association is particularly important. Specifically, it can be divided into two categories: disease-causing and disease-modifying. The former has a direct causal relationship with tumorigenesis, such as EGFR mutations and ALK gene translocations; the latter, while not the direct cause of tumorigenesis, can influence disease progression and thus produce therapeutic effects, such as PD-1/PD-L1 and CDK4/6. These two types of targets require different considerations during evaluation.

For disease-causing targets, the selectivity for subtypes or mutants directly impacts the drug's value and safety. For example, BCL2, a target related to apoptosis, involves the balance between anti-apoptotic and pro-apoptotic signals. Family members like MCL-1 are closely associated with resistance to BCL-2 inhibitors, while BCL-XL is involved in platelet function regulation. Therefore, a more detailed analysis of family members or subtypes in relation to efficacy, tolerance, and even safety is required.

II. Target Information Sources and Evaluation Strategies.

In the exploration of drug targets, pipeline drug information and patent information are currently the two primary sources, with journal literature serving as an important supplement. During evaluation, the balance between target novelty and maturity, the selection of reference compounds, and structural differentiation strategies are critical factors influencing project quality. Additionally, some companies leverage biological sample analysis data, such as gene or protein expression data, to mine innovative targets through bioinformatics methods. Developing small molecule drug projects based on such innovative targets requires initial compounds obtained through technologies like DNA-encoded compound libraries or molecular simulations. Thus, the part of target evaluation information related to subsequent activity characterization experiments becomes even more important.

III. Research Trends in Existing Oncology Drug Targets.

Based on pipeline drug project information, one can understand the considerations and challenges in current small molecule oncology drug project evaluations. Using Clarivate's Cortellis database, researchers analyzed over 3,900 small molecule oncology drug projects recorded since 2007. The distribution of targets in Phase III clinical trials shows a polarized situation: on one side are well-known kinase targets like VEGFR, PDGFR, FGFR, PI3K, AKT, and MEK; on the other are relatively less prominent new targets, such as Exportin1, P53-MDM2 protein-protein interactions, and NEDD8 activating enzyme related to protein degradation.

Among the numerous Phase II and Phase I projects, kinase targets still dominate the top 30, including EGFR family members, MET, PI3K, CDK4/6, BTK, ALK, and others, as well as epigenetics-related targets like BRD4, LSD, and HDAC6. Additionally, some innovative targets have advanced to Phase II validation, particularly those related to tumor immunotherapy, such as A2AR, Axl/Tyro3/Mer family, CD73, TLR4/7/8, small molecule inhibitors targeting PD-1/PD-L1 interactions, DNA damage repair-related CHK1 and WEE1, RNA translation-related MNK1/2, and cell cycle regulation-related CDK7.

In Phase I projects, the number of mature target-related projects is declining, while new target projects are increasing, indicating more innovative projects are advancing to clinical stages. Examples include apoptosis-related MCL1, tumor immunotherapy-related STING, epigenetic targets like H3K79 methyltransferase, SETMYND domain-containing protein 3, and PLK4 from the PLK family. Patent disclosures further confirm that current R&D strategies primarily follow publicly disclosed hot targets abroad. Patents targeting EGFR and BRD4 topped the list in 2016 and 2017 but declined by 2018, while those targeting HDAC6 and CDK4/6 increased yearly. For the much-discussed IDO target, numerous compound patents were still disclosed in the first half of 2018.

Preclinical projects involve numerous and dispersed targets, reflecting the increasing disease segmentation driven by precision medicine concepts, leading to more potential targets for specific disease subsets. For years, small molecule oncology drug innovation has been guided by the "oncogene addiction" concept. However, some targets with low tumor incidence and distribution across different tumors face significant challenges due to clinical development difficulties and market regulations. Meanwhile, many potential "tumor driver" targets remain under-validated. Additionally, targets identified solely from pipeline information are relatively isolated, making cross-comparisons difficult. Insufficient information disclosure and homogenization issues result in projects lacking clear differentiation strategies in compounds and patents. Coupled with the lack of breakthrough research in some complex diseases, the difficulty of project initiation research further increases.

IV. Construction and Application of Disease-Drug Mechanism Information Networks.

A renowned pharmacologist once said, "All new drug development should be based on a deep understanding of existing drugs." Guided by this concept, constructing information networks of drug mechanisms and disease-target associations helps deepen disease understanding and effectively discover potential targets. Starting from diseases, understanding changes in the body and organs during disease progression, delving into molecular and cellular pathological processes, and using pathway analysis to guide drug efficacy and safety evaluations can identify practical clinical needs, clarify target-disease associations, and assess the strength of supporting evidence.

Leveraging disease and drug mechanism network information can optimize target classification and comparison, clarify overall therapeutic directions, identify key nodes in different pathways, and explore methods to enhance efficacy and improve tolerance. Milestone literature in oncology is crucial for deepening understanding of tumor nature and constructing information networks. Additionally, combining technological advancements to evaluate target intervention methods from different perspectives can drive project innovation. For example, protein-protein interaction drugs can influence the assembly of protein complexes in epigenetics, thereby modulating their catalytic activity. Network information can also explore synthetic lethality strategies based on drug combinations, fostering more R&D opportunities.

V. Conclusion.

In the current R&D environment, the limitations of relying solely on pipeline and patent information for new project discovery are becoming increasingly apparent. The future drivers of innovative drug development lie in the integration of disease and drug mechanism understanding, the practical application of innovative experimental concepts and technologies, and close collaboration among R&D departments. Only through multi-directional integration of information, technology, and teams can R&D efficiency be fully enhanced and drug innovation driven. U-Pharm provides CDK2/CycE1 Protein, suitable for establishing CDK2/CycE1 kinase activity assays, in vitro screening and evaluation of cell cycle-targeted inhibitors, and research on CDK2 signaling pathway mechanisms.

This article is reviewed and published by the technical expert team of UA

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

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