Transcription-related Targets in Drug Discovery

Expert-driven In Silico Drug Discovery Solutions
21 February 2023
Svitlana Kondovych
Senior Researcher

It is established that transcription factors (TFs) are proteins that initiate and control gene expression and transcription from DNA to RNA through binding to specific sequences of DNA. TFs play central roles in the regulation of the entire cell’s genome functionality: cell division and differentiation, growth, development, responses to internal and external stimuli, and death [1]. The presence of TFs enables unique expression of the common genetic code in different cell types and determines the life of individual cells, as well as the whole organism. No wonder that deregulated TF function and corresponding misregulation of gene expression programs causes the progression of a broad range of diseases, including cancer, diabetes, neurological, autoimmune, inflammatory disorders, cardiovascular disease, and parasitic infections [2-4]. TF dysfunction related to such disorders may manifest through various mechanisms, such as up- or down-regulation of effector genes or changes in target genes (Fig. 1).

Changes in the TF transcriptional profile that lead to dysregulation of an effector gene driving a disease state.

Figure 1. Changes in the TF transcriptional profile that lead to dysregulation of an effector gene driving a disease state. Adopted from [4].

Despite their abundance and crucial biological role, TFs were long considered to be “undruggable” – impossible to target and modulate by small organic molecules – except for ligand-activated nuclear receptors, which are “druggable”, or accessible to conventional drug design [1, 4-5]. The challenges associated with targeting by small-molecule ligands are due to the complexity of TFs, intrinsic disorder, and absence of natural binding pockets. However, the increased knowledge of structure, function, and binding dynamics of TFs, as well as methodological advances in chemical biology approaches, such as targeted protein degradation, made it possible to develop novel transcription-related therapies [2-4,6].

In addition to the above-mentioned (and limited to nuclear receptors) direct targeting of TFs through binding of a ligand-based molecule in an activation/inhibition pocket, indirect targeting of TFs can be realized through affecting critical stages of the transcription process (Fig. 2). Major strategies to indirectly modulate DNA-binding TFs include their activation or inhibition at different levels of transcription [1]: expression level (epigenetic control), protein degradation, protein/protein interaction, protein/DNA binding level. Within these approaches, a number of small-molecule drug candidates were identified as TF activity inhibitors [7,8], which paved a way to extensive TF-based drug development studies and opened new therapeutic opportunities.

Mechanisms of targeting transcription factors (TFs).

Figure 2. Mechanisms of targeting transcription factors (TFs). Adopted from Ref.[3].

To promote the transcription-related drug discovery, Life Chemicals has created distinctive collections of drug-like screening compounds competent for TF modulation research. These encompass the following:

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  1. Lambert M, Jambon S, Depauw S, David-Cordonnier M-H. (2018). Targeting Transcription Factors for Cancer Treatment. Molecules. 23(6):1479. doi:10.3390/molecules23061479
  2. Papavassiliou, K. A., & Papavassiliou, A. G. (2016). Transcription Factor Drug Targets. Journal of Cellular Biochemistry, 117(12), 2693–2696. doi:10.1002/jcb.25605
  3. Walters, H. A., & Temesvari, L. A. (2021). Target acquired: transcriptional regulators as drug targets for protozoan parasites. International Journal for Parasitology, 51(8), 599–611. doi:10.1016/j.ijpara.2020.12.007
  4. Henley, M.J., Koehler, A.N. (2021). Advances in targeting ‘undruggable’ transcription factors with small molecules. Nat Rev Drug Discov 20, 669–688. doi:10.1038/s41573-021-00199-0
  5. Papavassiliou, A.G. (1997). Transcription Factor-Based Drug Design in Anticancer Drug Development. Mol Med 3, 799–810. doi:10.1007/BF03401717
  6. Mitra P. (2020). Targeting transcription factors in cancer drug discovery. Explor Target Antitumor Ther. 1:401-12. doi:10.37349/etat.2020.00025
  7. Hagenbuchner J., Ausserlechner M.J. (2016). Targeting transcription factors by small compounds—Current strategies and future implications. Biochemical Pharmacology, 107: 1-13. doi:/10.1016/j.bcp.2015.12.006
  8. Chen A., Koehler A.N. (2020). Transcription Factor Inhibition: Lessons Learned and Emerging Targets. Trends in molecular-medicine, 26,5: 508-518. doi:/10.1016/j.molmed.2020.01.004
21 February 2023, 13:30 Svitlana Kondovych Computational Chemistry

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