Transcription Factors (TFs) are central regulators of gene expression and are implicated in numerous diseases, including cancer, autoimmune, neurological, and metabolic disorders. Once considered 'undruggable,' TFs are now therapeutically targeted using selective modulators, degraders, and innovative approaches like PROTACs.
Recent FDA approvals, such as belzutifan (for VHL-associated renal cell carcinoma and elacestrant (for breast cancer), highlight clinical progress. PROTACs and direct small-molecule inhibitors—like those for FOXA1—are expanding treatment options. Artificial intelligence, CRISPR, RNA interference, and engineered modulators promise even greater precision. These advances are transforming treatment paradigms, offering new hope for patients with previously untreatable or difficult-to-treat diseases.
The master regulators
The human genome encodes approximately 1,600 TFs, one of the largest protein families and an intricate regulatory network that controls when, where, and how genes are expressed 1. These molecular machines achieve regulatory specificity through diverse DNA-binding domains that recognize distinct nucleotide sequences, determining cellular fate decisions and responses to pathological conditions (Figure 1)1–3.
Figure 1. The Human TF Repertoire1. (A) Schematic of a prototypical TF. (B) Number of TFs and motif status for each NA-binding domain (DBD) family. Inset displays the distribution of the number of C2H2-ZF domains for classes of effector domains (KRAB, SCAN, or BTB domains); “Classic” indicates the related and highly conserved SP, KLF, EGR, GLI GLIS, ZIC, and WT proteins.
Disease mechanisms associated with transcription factors (TFs)
Over 19% of the TFs have been shown to be associated with at least one disease phenotype1. Cancer represents the most extensively studied disease category involving transcription factor dysregulation, with multiple TFs driving distinct oncogenic mechanisms2,4–6. Hypoxia-inducible factors (HIFs), MYC, ETS-1, and β-catenin function as master regulators that constitutively activate oncogenic pathways, promoting tumor cell proliferation, survival, altered metabolism, and metastatic spread5. In contrast, p53 mutations impair critical tumor suppression mechanisms, enabling uncontrolled cellular growth across breast, prostate, and hematologic malignancies2. Hormone-dependent cancers rely heavily on FOXA1 and ESR1 for tumorigenesis in breast and prostate tissues, while STAT3 sustains cancer cell survival and facilitates immune evasion across multiple cancer types5. Additionally, BRD4 and KLF5 regulate oncogenic transcription programs specifically in basal-like breast cancer5.
Autoimmune diseases involve TFs that disrupt immune homeostasis through various mechanisms. Tcf1 and Lef1 maintain CD8+ T-cell identity, and their disruption skews CD4+/CD8+ ratios, compromising immune function7. STAT6 and STAT3 mediate inflammatory pathways in atopic dermatitis and hidradenitis suppurativa, while IRAK4 drives inflammation in hidradenitis suppurativa, making it an attractive target for degrader therapies8. The NF-κB/STAT/AP-1 axis synergistically activates pro-inflammatory genes in synovial cells, perpetuating joint destruction in rheumatoid arthritis9–11.
Neurological disorders feature TFs controlling neural development and survival pathways. POU3F2 regulates neocortical development genes, with dysregulation linked to schizophrenia and bipolar disorder12. FOXO family members modulate neuronal survival and autophagy, contributing to neurodegeneration when dysfunctional13. TFEB controls lysosome biogenesis, and its impaired function exacerbates Alzheimer's pathology14,15.
Metabolic diseases mainly involve TFs regulating glucose homeostasis and adipose tissue function. HNF1α and HNF4α control insulin production and glucose metabolism, with mutations causing maturity-onset diabetes (MODY)15. HOXA5 regulates adipocyte differentiation and distribution, driving obesity-related inflammation and insulin resistance when deficient16. FOXM1 mediates diabetic complications through endothelial dysfunction17.
Cardiovascular diseases feature BRD4, EP300, and MED1, which stabilise DNA loops regulating cardiac gene expression18. Their dysregulation drives congenital heart disease and atherosclerosis through disrupted cardiac transcriptional programs18.
TFs as Therapeutic Targets
Unlike enzymes with well-defined active sites, TFs function through relatively featureless protein-protein and protein-DNA interaction surfaces. Historically, TFs have been considered “undruggable” due to their lack of traditional binding pockets suitable for small molecule drugs19. Nevertheless, research advancements have been made to overcome the hurdles.
In the 1970s, the creation of tamoxifen—a selective estrogen receptor modulator—revolutionized breast cancer treatment by showing that TFs could be targeted with competitive antagonists 20,21. This marked one of the first rational drug design strategies for directly inhibiting TFs. Similarly, extensive research has focused on developing compounds that block hypoxia-inducible factor 1 (HIF-1) activation for cancer therapy 22.
Nuclear hormone receptor modulators and indirect targeting strategies remain the gold standard for TF therapeutics 23. Selective estrogen receptor modulators (SERMs) and degraders (SERDs), including tamoxifen, fulvestrant, and the recently approved elacestrant, are the most successful agents for hormone receptor-positive breast cancer. SERMs act as competitive antagonists to block receptor activityblock receptor activity, while SERDs induce receptor degradation through ubiquitin-proteasome pathways21. Recently, belzutifan—the first direct small molecule inhibitor of the HIF-2α—was approved in 2021 for von Hippel-Lindau (VHL) disease 24. This breakthrough demonstrates the potential of directly targeting TF protein-protein interaction domains 25. The FDA has approved seven drugs targeting TF for the treatment of cancers, autoimmune diseases, and cardiovascular diseases (as shown in Table 1).
Table 1. Featured FDA-Approved TF Inhibitors
Breakthroughs in TF Therapeutics
The past decade has witnessed remarkable progress in TF therapeutics, driven by innovative approaches including proteolysis targeting chimeras (PROTACs), direct TF inhibitors, and combination strategies.
Breakthroughs in PROTACs
PROTACs have been the most clinically advanced approach for targeting TFs since they were first designed by Sakamoto and Crews in 20018,32–34. These bifunctional molecules simultaneously bind target proteins and E3 ubiquitin ligases, facilitating selective protein degradation through the ubiquitin-proteasome system33. TF-PROTACs have demonstrated efficacy against NF-κB and E2F, opening new therapeutic avenues for multiple diseases34.
Figure 2. PROTAC (proteolysis-targeting chimera) mechanism: a bifunctional molecule recruits E3 ligase to the protein of interest (POI), triggering its ubiquitination and subsequent degradation by the proteasome 32.
Figure 2. PROTAC (proteolysis-targeting chimera) mechanism: a bifunctional molecule recruits E3 ligase to the protein of interest (POI), triggering its ubiquitination and subsequent degradation by the proteasome 32.
Table 2 highlights PROTAC compounds targeting TFs that are currently in clinical trials 35. Notably, ARV-471 (vepdegestrant), which degrades the estrogen receptor, and BMS-986365 (CC-94676), targeting the androgen receptor, have shown strong clinical efficacy with protein degradation rates over 90% in cancer patients 36. In February 2024, the FDA granted vepdegestrant Fast Track designation for treating ER+/HER2- advanced or metastatic breast cancer in adults previously treated with endocrine therapy 37.table 1
Table 2 PROTACs Targeting TFs in Clinical Trials (Source: https://synapse.zhihuiya.com/)
Breakthroughs in Small Molecules (H3)
Recent years have seen significant strides in targeting challenging transcription factors through diverse mechanisms. Small molecule inhibitors targeting STAT3 have made notable progress, with several compounds showing promise in clinical trials 38,39. While no STAT3 inhibitors are yet FDA-approved, the development of STAT3 PROTACs is a promising strategy to address the challenges of directly targeting this TF 40. NF-κB pathway inhibitors have also advanced through clinical development, with several small molecules targeting various components of this key inflammatory TF pathway 41. These agents are especially promising for treating inflammatory diseases, certain cancers, and antuimmune diseases driven by NF-κB. Notably, Direct Targeting of FOXA1: WX-02-23 is a breakthrough as the first small molecule to directly bind TF FOXA1, covalently targeting a cryptic cysteine residue (C258) when FOXA1 is DNA-bound, altering its binding specificity and demonstrating that TFs can be drugged via allosteric modulation 19.
Future Directions
The future of therapeutics targeting TFs focuses on combination therapies and precision medicine. Artificial intelligence is accelerating drug discovery by using machine learning to predict binding sites, optimize drug design, and identify patient-specific targets 42–44. Emerging technologies—such as CRISPR-based approaches 45, RNA interference46, and engineered TF modulators47 are set to transform the field. These platforms enable highly precise targeting of specific TF functions while reducing off-target effects.
Featured Products of Transcription Protein
Conclusion
TF therapeutics have moved from concept to clinical reality, with multiple compounds reaching late-stage trials and regulatory approval 32. Advances in drug discovery, precision delivery, and personalized medicine now allow for highly specific targeting of disease-driving mechanisms 48. As these therapies prove both safe and effective in oncology, autoimmune, and genetic diseases, they are poised to redefine treatments and bring new hope to patients with previously untreatable conditions.
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