Basic helix-loop-helix (BHLH) TFs

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Basic helix-loop-helix (BHLH) TFs

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The basic helix-loop-helix (bHLH) structural motif is characteristic of a family of generally dimeric transcription factors (TFs). Basic amino acids in the helices facilitate DNA binding. Dysregulated TFs activity is a significant driver of cancer development, progression, and therapy resistance. Certain TFs are therefore considered as molecular targets for the development of anti-tumour drugs.

Targets

3349

aryl hydrocarbon receptor C Show summary »« Hide summary More detailed page go icon to follow link

aryl hydrocarbon receptor nuclear translocator Show summary »« Hide summary

Target Id

3349

Nomenclature

aryl hydrocarbon receptor nuclear translocator

Previous and unofficial names

HIF-1beta | HIF-1β | hypoxia inducible factor 1 subunit beta

Genes

ARNT (Hs), Arnt (Mm), Arnt (Rn)

Ensembl ID

ENSG00000143437 (Hs), ENSMUSG00000015522 (Mm), ENSRNOG00000031174 (Rn)

UniProtKB AC

P27540 (Hs), P53762 (Mm), P41739 (Rn)

Ligands

NEO-811 (Binding) (Molecular glue degrader)

Comment

The ARNT protein (also known as HIF-1β) is the obligate dimerization partner for the HIF-1α and HIF-2α transcriprion factors. It is being investigated as a novel oncology drug target, with the development of targeted protein degraders in progress [13]. NEO-811 [9] is a clinical stage ARNT-selective degrader.

MYC proto-oncogene, bHLH transcription factor Show summary »« Hide summary

Target Id

3335

Nomenclature

MYC proto-oncogene, bHLH transcription factor

Previous and unofficial names

Myc proto-oncogene protein | bHLH transcription factor | c-Myc | MYCC | v-myc avian myelocytomatosis viral oncogene homolog

Genes

MYC (Hs), Myc (Mm), Myc (Rn)

Ensembl ID

ENSG00000136997 (Hs), ENSMUSG00000022346 (Mm), ENSRNOG00000004500 (Rn)

UniProtKB AC

P01106 (Hs), P01108 (Mm), P09416 (Rn)

Ligands

MP-16 (Binding) (PROTAC degrader) [1]

Comment

The protein eccoded by the MYC gene is an intensely studied transcription factor with well established roles in cell proliferation, differentiation, cell cycle, metabolism, apoptosis. Alternative initiation codons permit translation of isoforms with distinct N-termini. MYC dyregulation is implicated in a large percentage of human cancers and therefore it is being explored as a target for the development of anti-tumour therapeutics [6-8,16,20-21]. Mechanistic approaches to reducing aberant MYC activity are principally indirect and include targeting upstream and downstream pathway regulators such as BRD4, PI3K, HDACs, CDK6/9, BET and Aurora kinases to suppress MYC expression and function, PROTAC-mediated degradation of regulatory proteins such as bromodomain and extraterminal (BET) proteins [17], and disruption of MYC/MAX heterodimerisation and subsequent binding to the promoters of MYC target genes [4]. PROTACs using aptamers and nucleotides to directly promote MYC degradation have been used to demonstrate the anti-tumour potential of selective elimination of MYC protein [1,11,14,18]. Diamond et al. (2025) have reported a novel approach that uses a small molecule (proprietary name Interdictor™) to directly and selectively target MYC protein as it is translated at the ribosome [5].

oligodendrocyte transcription factor 2 Show summary »« Hide summary

Target Id

3332

Nomenclature

oligodendrocyte transcription factor 2

Genes

OLIG2 (Hs), Olig2 (Mm), Olig2 (Rn)

Ensembl ID

ENSG00000205927 (Hs), ENSMUSG00000039830 (Mm), ENSRNOG00000028658 (Rn)

UniProtKB AC

Q13516 (Hs), Q9EQW6 (Mm)

Inhibitors

CT-179 [12]

OLIG2 inhibitor B01 [23]

Comment

OLIG2 is a CNS-specific transcription factor that is involved in oligodendrocyte differentiation and neural development. It is not expressed in healthy adult brain, but is highly expressed in some CNS tumours where it acts as oncogenic driver. OLIG2 is being investigated as a therapeutic target in glioblastoma and medulloblastoma [10,23,23].

transcription factor 4 Show summary »« Hide summary

Target Id

3326

Nomenclature

transcription factor 4

Previous and unofficial names

class B basic helix-loop-helix protein 19 (bHLHb19) | E2-2 | immunoglobulin transcription factor 2 (ITF2) | SEF2-1B | SL3-3 enhancer factor 2

Genes

TCF4 (Hs), Tcf4 (Mm), Tcf4 (Rn)

Ensembl ID

ENSG00000196628 (Hs), ENSMUSG00000053477 (Mm), ENSRNOG00000012405 (Rn)

UniProtKB AC

P15884 (Hs), Q60722 (Mm), Q62655 (Rn)

Endogenous ligands

β-catenin (CTNNB1, P35222) (Binding) (Formation of the beta-catenin/TCF4 transcription complex) [19]

Comment

A transcription factor that preferentially binds to either 5'-ACANNTGT-3' or 5'-CCANNTGG-3' to initiate transcription. Participates in initiating neuronal differentiation.

References

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1. Ai M, Ma H, He J, Xu F, Ming Y, Ye Z, Zheng Q, Luo D, Yang K, Li J et al.. (2024) Targeting oncogenic transcriptional factor c-myc by oligonucleotide PROTAC for the treatment of hepatocellular carcinoma. Eur J Med Chem, 280: 116978. [PMID:39447458]

2. Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA. (1991) Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci USA, 88 (21): 9543-7. [PMID:1658785]

3. Bobrovs R, Olafsen NE, Ahrling SS, Matthews J. (2026) Aryl Hydrocarbon Receptor Pharmacology - Mechanisms, Ligands, and Therapeutic Potential. Pharm Rev, Epub ahead of print. DOI: 10.1016/j.pharmr.2026.100146

4. Chen H, Song J, Wang Y, Peng Z, Zeng H, Zhou H, Shang W, Chen Y. (2026) Alternative Strategies of Reducing MYC Expression for the Treatment of Cancers. J Med Chem, [Epub ahead of print]. [PMID:41489490]

5. Diamond PD, Sauer PV, Holm M, Swanson-Swett CJ, Ferguson L, Bratset NM, Wienker GW, Sim JS, Adams HK, Kenner L et al.. (2025) Context-dependent translation inhibition as a novel oncology therapeutic modality. bioRxiv, Preprint. DOI: 10.1101/2025.01.09.632223v1

6. Duffy MJ, O'Grady S, Tang M, Crown J. (2021) MYC as a target for cancer treatment. Cancer Treat Rev, 94: 102154. [PMID:33524794]

7. Duffy MJ, Tang M, Crown J. (2025) MYC as a Target for Cancer Treatment: from Undruggable to Druggable?. Target Oncol, 20 (5): 791-801. [PMID:40815489]

8. Garralda E, Beaulieu ME, Moreno V, Casacuberta-Serra S, Martínez-Martín S, Foradada L, Alonso G, Massó-Vallés D, López-Estévez S, Jauset T et al.. (2024) MYC targeting by OMO-103 in solid tumors: a phase 1 trial. Nat Med, 30 (3): 762-771. [PMID:38321218]

9. Griffin JR, Liu X, Tellew JE. (2025) Substituted (piperidin-4-yl)-1,5-naphthyridine and (piperidin-4-yl)quinoline derivatives and uses thereof. Patent number: WO2025097090A1. Assignee: Neomorph Inc. Priority date: 02/11/2024. Publication date: 08/05/2025.

10. Kapoor S, Kouznetsova VL, Kesari S, Tsigelny IF. (2025) Epigenetic Regulation of OLIG2 in Glioblastoma: Mechanisms and Therapeutic Targets to Combat Treatment Resistance. J Mol Neurosci, 75 (3): 112. [PMID:40885881]

11. Li X, Zhang Z, Gao F, Ma Y, Wei D, Lu Z, Chen S, Wang M, Wang Y, Xu K et al.. (2023) c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer. J Am Chem Soc, 145 (16): 9334-9342. [PMID:37068218]

12. Li Y, Lim C, Dismuke T, Malawsky DS, Oasa S, Bruce ZC, Offenhäuser C, Baumgartner U, D'Souza RCJ, Edwards SL et al.. (2025) Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179. Nat Commun, 16 (1): 1091. [PMID:39904981]

13. Sabnis RW. (2026) Novel Compounds as ARNT Degraders for Treating Cancer, in Particular, Hematological Cancer. ACS Med Chem Lett, 17 (2): 300-301. [PMID:41704380]

14. Samarasinghe KTG, An E, Genuth MA, Chu L, Holley SA, Crews CM. (2022) OligoTRAFTACs: A generalizable method for transcription factor degradation. RSC Chem Biol, 3 (9): 1144-1153. [PMID:36128504]

15. Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C, Coquery CM, Neil J, Pryor WM, Mayhew D et al.. (2017) Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J Invest Dermatol, 137 (10): 2110-2119. [PMID:28595996]

16. Wang C, Zhang J, Yin J, Gan Y, Xu S, Gu Y, Huang W. (2021) Alternative approaches to target Myc for cancer treatment. Signal Transduct Target Ther, 6 (1): 117. [PMID:33692331]

17. Wang H, Wu X, Gao J, Chen S, Zhou Z, Zhang L, Liu B, Wei M. (2025) Targeting Myc through BET-PROTAC elicits potent anti-lymphoma activity in diffuse large B cell lymphoma. Invest New Drugs, 43 (3): 621-633. [PMID:40307411]

18. Wang Y, Yang G, Zhang X, Bai R, Yuan D, Gao D, He Q, Yuan Y, Zhang X, Kou J et al.. (2024) Antitumor Effect of Anti-c-Myc Aptamer-Based PROTAC for Degradation of the c-Myc Protein. Adv Sci (Weinh), 11 (26): e2309639. [PMID:38682443]

19. Wang Z, Zhao T, Zhang S, Wang J, Chen Y, Zhao H, Yang Y, Shi S, Chen Q, Liu K. (2021) The Wnt signaling pathway in tumorigenesis, pharmacological targets, and drug development for cancer therapy. Biomark Res, 9 (1): 68. [PMID:34488905]

20. Whitfield JR, Soucek L. (2021) The long journey to bring a Myc inhibitor to the clinic. J Cell Biol, 220 (8). [PMID:34160558]

21. Whitfield JR, Soucek L. (2025) MYC in cancer: from undruggable target to clinical trials. Nat Rev Drug Discov, 24 (6): 445-457. [PMID:39972241]

22. Wilkinson IVL, Perkins KJ, Dugdale H, Moir L, Vuorinen A, Chatzopoulou M, Squire SE, Monecke S, Lomow A, Geese M et al.. (2020) Chemical Proteomics and Phenotypic Profiling Identifies the Aryl Hydrocarbon Receptor as a Molecular Target of the Utrophin Modulator Ezutromid. Angew Chem Int Ed Engl, 59 (6): 2420-2428. [PMID:31755636]

23. Xu Z, Xi Y, Guo Y, Wang C, Shi Y, Sun D, Zhang Y, Ye F, Xu X, Wang X. (2025) Discovery of novel pyrimidine-4,6-diamine-based OLIG2 inhibitors as potent anti-glioblastoma agents. Eur J Med Chem, 298: 118009. [PMID:40763665]

How to cite this family page

Database page citation:

Basic helix-loop-helix (BHLH) TFs. Accessed on 16/06/2026. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1121.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Gibb AJ, Kelly E, Mathie AA, Peach CJ, Veale EL, Cidlowski JA, Davenport AP, Fabbro D, Spedding M, Striessnig J, Armstrong JF, Buneman OP, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Introduction and Other Protein Targets. Br J Pharmacol. 182: S1-S23.