Design, synthesis, and biological evaluation of 2-(2-oxoindolin-3-ylidene)hydrazinecarbothioamides as a potential EGR-1 inhibitor for targeted therapy of atopic dermatitis

Atopic dermatitis (AD) or atopic eczema is one of the most prevalent inflammatory skin diseases worldwide. The Global Burden of Disease Study estimated that the general prevalence of AD is 20 % among children and 10 % in adults [1]. AD is characterized by intense pruritus and frequent skin barrier dysfunction [2] and is associated with numerous co-occurring chronic conditions, such as asthma, allergic rhinitis, and cardiovascular disease [3].

However, the precise etiology of AD remains unclear. Accumulating evidence has demonstrated that AD development can be affected by genetic and environmental elements, abnormalities in the epidermal barrier, and impaired skin immunity [4], [5]. Usually, AD pathogenesis is predominantly triggered by various inflammatory cytokines produced by keratinocytes and infiltrating immune cells in the skin lesions, specifically mast cells, neutrophils, CD4 + T helper (Th) lymphocytes (Th2, Th22, and Th17 cells), and macrophages/monocytes [6], [7], [8].

During the acute phase of atopic dermatitis, thymic stromal lymphopoietin (TSLP) is released from keratinocytes in response to allergen exposure, microbial infection, and injury [9] and activates Th2 cells to produce (IL)-4, IL-5, IL-13, IL-31, and IL-33 [1], [4], [10]. Severe itching is an important clinical feature of AD. Keratinocyte-derived cytokines (IL-18, IL-1β, IL-33, TSLP, and IL-25) and Th2-derived cytokines (IL-4, IL-13, and IL-31) directly stimulate sensory neurons, which promotes itching [11], [12], [13]. During the transition to the chronic phase, scratching further aggravates itching by causing continued irritation of skin lesions and impairing skin barrier function, resulting in a vicious itching/scratching cycle [14].

The gene EGR1 encodes a transcription factor EGR-1 with three Cys2-His2 type zinc-finger DNA binding domains [15]. It responds rapidly to various external stimuli and plays a crucial role in physiological processes such as cell death, replication, and inflammation [16], [17], [18], [19], [20]. EGR-1 expression is elevated in the wound region of the skin [21], psoriatic skin lesions [22], and mouse skin lesions induced by the topical application of 2,4-dinitrochlorobenzene (DNCB) [23]. EGR-1 regulates the expression of thymic stromal lymphopoietin (TSLP), psoriasin (S100A7), and KLK7 in response to specific inflammatory cytokines [24], [25], [26],

Although the pathophysiological role of EGR-1 in AD progression of AD has been well-characterized, there are currently no specific chemotherapeutic drugs targeting this protein. Previously, we identified ((E)-2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-6-nitro-4H-chromen-4-one (AB1711) as a targeting agent that selectively binds to the zinc finger DNA-binding domain of EGR-1, preventing its DNA-binding capability and suppressing atopic dermatitis-like skin lesions [23]. However, the potential of the AB1711 compound as a therapeutic agent has been limited by its poor solubility (logP = 5.45) and low ED50 value for the inhibition of EGR-1 DNA-binding activity at the cellular level (∼30 μM) [23], making it unsuitable for further development.

The purpose of this study was to identify novel substances that can specifically target the EGR-1 DNA-binding domain through the utilization of AB1711 derivatives. We identified three hydrazinecarbothioamide derivatives, including (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazine carbothioamide (referred to IT21), (Z)-2-(6-methoxy-2-oxoindolin-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbothioamide (referred to IT23) (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (referred to IT25). These compounds effectively prevented EGR-1 DNA-binding activity in vitro and potentially reduced skin inflammation and sensory nerve growth in AD-like skin lesions in BALB/c mice topically challenged with DNCB.

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