Innovative Drug Candidates for Skin Diseases

Keloids are overgrowths of scar tissue that extend beyond the original wound boundaries, often resulting in itchy, painful scars. These benign skin tumors form due to genetic and environmental factors, with individuals of African, Hispanic, and Asian descent being more susceptible. Common triggers include piercings, surgical incisions, acne, and minor traumas, particularly on the chest, shoulders, and earlobes. Although several treatments are available, including surgical removal, steroid or 5-fluorouracil injections, and laser therapy, their efficacy is inconsistent, and keloids often recur.

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Consequently, there's a demand for new treatments targeting the underlying molecular mechanisms driving keloid formation and progression.

Recent research indicates that keloids are linked to the activation of fibroblasts influenced by factors like hypoxia and TGF-β signaling. Beyond the familiar SMAD pathway linked to TGF-β, the non-canonical MEK/ERK pathway enhances fibroblast activity and growth. Cells like T- lymphocytes and macrophages release growth factors, including PDGF and VEGF, amplifying the MEK/ERK signaling and fibroblast proliferation. As such, inhibition of downstream MEK/ERK signaling may serve as a viable therapeutic strategy in treating keloids.

 

While there are four FDA-approved MEK1 inhibitors available, systemic administration frequently results in undesirable side effects, such as cardiotoxicity. Demand persists for a MEK1 inhibitor tailored for topical or intralesional use. We hypothesize that local administration of a MEK1 inhibitor will attenuate fibroblast activation and promote regression of lesions in PN, offering a targeted approach that could revolutionize the treatment paradigm for this condition.

 

Using a novel machine learning-based approach, we have designed two MEK1 inhibitors: NL350-01 and NL350-02. These compounds have enhanced pharmacokinetic and physiochemical characteristics with retained biological activity and are compatible with topical and injectable compositions. Preliminary in vitro studies involving human keloid fibroblasts with NL350-02 reveal low nanomolar range attenuation of ERK activation and a 3000-fold reduction in Ki-67 expression. Transcriptomic studies revealed pro-apoptotic, anti-proliferative, and anti-inflammatory changes post-treatment. We hypothesize MEK1 inhibition will promote similar effects on PN lesions, and local administration of NL350-01 and NL350-02 will promote lesion regression.

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