Investigating Thyroid Receptor β Therapy's Role in Combatting Androgenetic Alopecia

A review published in Drug Discovery Today explored the potential of targeting the thyroid receptor β (TRβ) for treating androgenetic alopecia. These researchers examined different mechanisms by which TRβ might work, highlighted promising drug candidates, and explored the relationship between the structure of a drug and its effectiveness on TRβ.¹

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Subtypes, Physiological Functions

The human body has 2 main thyroid hormone receptors: TRa and TRβ. Subtypes of TRa include TRa1, crucial for brain development, and TRa2, although its function remains unclear. The 3 subtypes of TRβ include TRβ1, which regulates development and T3, the natural thyroid hormone, effects; TRβ2, which regulates the hypothalamus, the pituitary gland, and vision; and TRβ3, whose function is still unclear.

Hair Growth Cycle

The hair growth cycle includes 3 primary phases: anagen, catagen, and telogen. The anagen phase consists of the active growth of the hair, as the generation of new hair shafts develop within the follicles; the catagen phase is the shortest phase of the cycle, and where cell division of follicular keratinocytes gradually stops; and in the telogen phase, the follicles release and shed the hair, which allows the beginning of a new anagen phase.

Mechanisms Associated With Anti-AGA Effects

Thyroid hormones have displayed significance in hair growth regulation, where patients with thyroid dysfunction have exhibited abnormal hair patterns.¹ Based on a Mendelian randomization study, alopecia is an autoimmune disease, resulting in higher risks of thyroid issues, especially hypothyroidism. This is mainly due to the common pathogenesis, genetic backgrounds, and inflammatory processes between alopecia and hypothyroidism.²

TRβ1 is the dominant form of thyroid receptor during human hair follicle growth.¹ TRβ agonists can implement anti-alopecia effects using the Wnt/β-catenin signaling pathway and the Sonic hedgehog signaling pathway.

The Wnt/b-catenin signaling pathway can induce the onset of anagen and regulates the hair cycle.³ There is evidence this pathway is significant to the role of morphogenesis and the regeneration of hair follicles.

Evidence of the Sonic hedgehog signaling pathway was found in relation to growth and morphogenesis of hair follicles.⁴ Although the induction of hair follicles is independent to Sonic hedgehog pathways, these pathways are essential for ingrowth of the epidermis and ultimately the morphogenesis of the hair shaft.

The researchers urged caution when stimulating TRβ to minimize TRa, which could increase adverse effects on the heart.¹

Activation of TRβ, Expression of TGF-β2

Transforming growth factor β2, a naturally occurring protein in the body, has been shown to stop hair growth by slowing down the division of hair follicle cells and speeding up their transition into the catagen phase. Treating hair loss with transforming growth factor β2 can reduce the activity of the germinal matrix cells, which are responsible for new hair growth.

Activation of TRβ, Expression of Cyclin D1

The thyroid receptor acts like a switch, turning on the production of cyclin D1. This happens through 2 important signaling pathways. The Wnt pathway is essential for hair growth because it activates β-catenin, which then interacts with other molecules in the nucleus to trigger cyclin D1 gene expression. Studies also show that stimulating the Sonic hedgehog pathway pushes hair follicles from a resting phase (telogen) to a growth phase (anagen).

Activation of TRβ, Hair Follicle Stem Cells

Hair follicle stem cells in the bulge region multiply during hair growth (anagen) and are activated by β-catenin and cellular myelocytomatosis oncogene protein. The bone morphogenetic protein signaling keeps hair follicle stem cells dormant, but thyroid hormone inhibits bone morphogenetic protein, promoting hair growth.

Activation of TRβ, Synthesis of Melanin in the Hair Follicle

Melanin production in hair follicles is increased by the thyroid receptor 3 hormone, especially during the growth phase, through the activation of pigment-producing cells known as melanocytes.

TRβ Agonists With Anti-AGA Activity

A review of research analyzed the discovery of KB-141, a molecule that strongly activates TRβ. In one study, TRβ showed it binds 14 times better compared with TRa.

Different variations of KB-141 were tested, and the researchers found that the length of a specific carboxylic acid side chain affects how well it binds; shorter chains like formic acid worked best, chlorine atoms in specific positions make it prefer one receptor over the other, and bromine boosted binding strength overall. Iodine wasn't used because the body easily removes it.

In one case, researchers tweaked KB-141 to target TRβ more effectively and achieved this by replacing iodine atoms with chlorine in key spots, shortening a side chain, and experimenting with different groups at a specific position. This led to several promising variations, some with dramatically higher selectivity for TRβ over TRa. Interestingly, some changes improved both binding strength and selectivity, while others had the opposite effect. These data provide valuable insights for designing future drugs that specifically target TRβ.

Another case had scientists modify KB-141 to target TRβ more effectively. The research focused on a key difference between TRa and TRβ receptors and designed a new structure with an amide group and a specific chain length. This modification led to a 33-fold increase in favoring TRβ, making it a promising candidate for future medications.

Some data showed researchers improved a series of compounds by adding a cyanoazauracil substitute, which made them more potent and targeted TRβ better. This led to the discovery of MGL-3196, a highly selective TRβ agonist. Although bromine atoms increased binding, safety concerns limited their use. However, for topical treatments like MGL-3196, bromine might be an option, like the existing drug KB-2115.

One form of research identified CS27109, a new molecule that strongly activates the TRβ involved in regulating metabolism. This new compound is even more effective than previous options (ie, MGL-3196) at targeting TRβ with minimal impact on TRa. Importantly, CS27109 also shows promise for heart safety, making it a potentially valuable candidate for future metabolic drugs.

Data showed evidence of scientists experimenting with different chemical groups attached to the molecule, finding that a methyl group on position 4 and a specific acid chain significantly improved binding to TRβ without affecting binding to TRa. This led to compound 26, which was more selective and potent than the existing drug, MGL-3196.

The researchers also explored modifying the acid side chain, inspired by the natural thyroid hormone T3. This approach yielded compound GC-1, the first noniodine-based thyroid hormone drug. They then improved selectivity for TRβ by adding a benzyl group, resulting in the highly selective GC-24.

There was evidence in one study where a hydroxyl group in one position hurt the drug's ability to reach its target, or bioavailability. Researchers also tested variations at other positions on the molecule and found sulfonamido and carboxamido groups worked best, especially with a piperidinyl nitrogen substituent. These variations led to highly selective molecules that strongly target TRβ receptors.

In some research, scientists analyzed a previous patent on indole compounds targeting the thyroid hormone receptor. Although the patent offered a starting point, it lacked details on specific modifications and their effects.

This gap presents an opportunity for improvement. The researchers found that adding an isopropyl group to a specific location on the indole ring and using oxygen as a linker significantly increased the compound's activity and selectivity for the desired receptor. Their approach led to compound 42, which exhibits strong activity and a preference for the target receptor.

One documented report of research showed scientists developed new molecules that target TRβ more effectively by starting with indane derivatives and identified KTA-439, which showed better selectivity for TRb. Further modifications were made, such as adding a hydroxyl group to improve selectivity even more (compound 47). This research highlights that manipulating the molecule's structure can significantly impact which receptor it targets.

Scientists created a TRβ-targeting molecule, MB07344, but it had issues with body distribution and breakdown. They improved this by making a new version, MB07811, that becomes the active molecule after it enters the liver. This new design is especially useful for topical treatments applied directly to the skin, where initial breakdown is not a major concern. The data also highlight how small changes in a molecule's structure can dramatically affect which thyroid receptor it targets.

Structure–Activity Relationships of TRβ Agonists

This review analyzes how scientists have extensively explored modifications to existing TRβ agonist structures, achieving a good understanding of how different substitutions affect selectivity and potency. However, the focus is shifting toward new chemical frameworks beyond the core diphenyl ether structure.

By delving deeper into the central skeleton of these molecules, scientists hope to design novel TRβ agonists with even greater selectivity and efficacy. This holds significant promise for developing safe and effective treatments for androgenetic alopecia. With the increasing prevalence of androgenetic alopecia at younger ages due to modern lifestyles, the discovery of TRβ agonists offer renewed hope for those seeking solutions to hair loss.

Although one such agonist (TDM105795) has entered clinical trials, further research is needed to fully understand the mechanism by which TRβ influences hair growth and to ensure highly selective drugs that avoid potential adverse effects.

References

1. Zhi J, Li F, Jiang X, Bai R. Thyroid receptor β: a promising target for developing novel anti-androgenetic alopecia drugs. Drug Discov Today. 2024;29(6):1-15. doi:10.1016/j.drudis.2024.104013
2. Santoro C. AA may increase risk of hypothyroidism, AG needs further investigation. The American Journal of Managed Care®. April 14, 2024. Accessed June 24, 2024. https://www.ajmc.com/view/aa-may-increase-risk-of-hypothyroidism-ag-needs-further-investigation
3. Shin DW. The molecular mechanism of natural products activating Wnt/β-catenin signaling pathway for improving hair loss. Life (Basel). 2022;12(11):1-18. doi:10.3390/life12111856
4. St-Jacques B, Dassule HR, Karavanova I, et al. Sonic hedgehog signaling is essential for hair development. Curr Biol. 1998;8(19):1058-1069. doi:10.1016/s0960-9822(98)70443-9

[This article was originally published by our sister publication, American Journal of Managed Care.]