Transcription Factor Inhibition

Transcription factors are proteins that control the DNA transcriptional process by selectively binding to a target sequence in the promoter region of the relevant gene to stimulate or inhibit transcription. They work by modifying the activity of RNA Polymerase II (Pol II) to ensure that transcription occurs (or not) at the appropriate time and place in the genome. Cancer therapies based on inhibiting the transcription of oncogenes such as C-Мус, HIF-1, NFkB, and STAT-3 have been envisaged. A number of small molecules inhibitors have been reported such as alvocidib, echinomycin, PBD molecules

Mechanism of action of quarfloxin (Taken from Balasubramanian S, Hurley LH, Neidle S (2011). “Targeting G-quadruplexes in gene promoters

FIGURE 5.87 Mechanism of action of quarfloxin (Taken from Balasubramanian S, Hurley LH, Neidle S (2011). “Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?” Nat Rev Drug Discov., 10 (4) 261-275. doi:10.1038/nrd3428. Copyright © 2011 Macmillan Publishers Limited).

(e.g., TSG-1301), and the hairpin polyamides that can bind to duplex DNA in a sequence-selective manner and inhibit transcription. Some of these molecules are described in Section, although none have reached the approval stage.

An alternative strategy known as PROTAC (proteolysis targeting chimeras) has been developed and is also described below. PROTAC is based on the design of a bifunctional complex that utilizes the ubiquitin-protease system to selectively degrade the transcription factor of interest, thus inhibiting the transcription process. One advantage of this approach is that it does not require a high concentration of the bifunctional complex to produce a therapeutic effect. Thus, PROTAC has become a promising strategy for treating a number of diseases including cancer. Small-Molecule Transcription Factor Inhibition

As described in Section, a number of small molecules have been identified that bind in the DNA minor groove and inhibit the binding of transcription factors whose role is to regulate which genes are transcribed at a particular time. Transcription factors contain subunits that directly target specific DNA sequences and initiate transcription, while other domains may modulate the rate and extent of transcription. Figure 5.88 is a schematic diagram of how small-molecule inhibitors can modulate the transcription process.

Some examples of genes suitable for down-regulation by this approach are provided in Table 5.2, and include c-Myc, HIF-1 and STAT-3. For example, C-Myc regulates cell proliferation, cell-cycle development, and oncogene transformation. During activation the Myc-Max complex attaches to the specific binding domain E-box motif at the promoter domain to trigger gene transcription, leading to termination of the core promoter through protein Miz-1.

Another example of a small-molecule transcription factor inhibitor is trabectedin (Yondelis™) which inhibits NF-Y/ PCAF. It was approved in 2015 by the FDA for the treatment of two subtypes of soft-tissue sarcomas, liposarcoma, and leiomyosarcoma. PROTAC

The PROTAC approach, initially described by Sakamoto, Crews, and Deshaies in 2001, is an acronym for proteolysis targeting chimera. The technology is based on a heterobifunctional small molecule composed of two active domains joined by a linker (Figure 5.89). Rather than working as a conventional inhibitor, a PROTAC works by inducing selective

Schematic diagram of the mechanism of action of small-molecule sequence-selective DNA-binding transcription factor inhibitors

FIGURE 5.88 Schematic diagram of the mechanism of action of small-molecule sequence-selective DNA-binding transcription factor inhibitors.


Examples of Small-Molecule Transcription Factor Inhibitors, Their General Structures and the Transcription Factors They Target.


General Structure

Transcription Factor Target

Alvocidib (Flavoperidol)




Oxazole-based peptidomimetic

STAT (SH2 domain)


Oxazole-based peptidomimetic

STAT (SH2 domain)


Nitrobenzo thiophene dioxide

STAT (SH2 domain)



HIF and Мус

NSC 50352



Hairpin polyamide




PBD conjugate





Mithramycin A



Platinum (II) complexes




Complex multi-ring


intracellular proteolysis. The heterobifunctional small molecule consists of two covalently linked protein-binding molecules, one capable of binding to the target transcription factor protein designated for degradation and the other designed to engage E3 ubiquitin ligases such as pVHL, Mdm2, beta-TrCPl, cereblon, and c-IAPl. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation by the 26S proteasome. As this does not block the binding site of the transcription factor, a high concentration of the PROTAC agent is not required to maintain its therapeutic effect, thus minimalizing toxicity and drug resistance. Another advantage of PROTAC is that it can target proteins which do not have enzymatic activities such as scaffolding proteins. However, one potential problem is the narrow E3 library available.

In 2019 the first androgen receptor (AR)-targeting PROTAC, ARV-110, entered Phase I clinical trials for prostate cancer. ARV-110 was the first PROTAC product targeted to the androgen receptor, working by degrading the nuclear receptor AR. It is now in Phase I clinical trials, and so far good tolerance and limited toxicity issues have been observed.

Another example is SD-36, a STAT3-targeting PROTAC agent, being developed for STAT3-sensitive cancers (Figure 5.90). SD-36 is a CRBN-based PROTAC which can selectively degrade STAT3. It contains a STAT3-targeting molecule (SI-109) which is thought to interact at the SH2 domain. In preclinical studies, it has provided a long-term suppression of leukemia and lymphoma in animal models with an acceptable level of tolerability.

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