The use of an interleukin β antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1β into active IL-1β, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.

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During our search for topically-active Caspase-1 inhibitors, we identified a novel class of potent inhibitors based on a 1,3,5-trisubstituted uracil motif equipped with an L-aspartate semi-aldehyde derived warhead. In the literature, the majority of Caspase-1 inhibitors possessing the same warhead have been designed and evaluated for oral administration as the ethyl acetal pro-drug form. For our topical program, the pro-drug acetal form was not fully hydrolysed in the skin and was unstable in many of our standard topical excipients, therefore, we were obliged to focus on the actual hemiacetal drug form of the molecule during our drug discovery program. Our work focuses on both the synthesis and achiral and chiral stability of the final drug molecules in topical excipients.

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Aspergillus species, a common saprophytic mold, seldom acts as a pathogen in immunocompetent hosts, and primary cutaneous involvement is even less. Herein, we report a patient of primary cutaneous aspergillosis harboring CARD9 mutations. The 45-year-old patient presented with a 37-year history of skin lesions on the face. The lesion was a soy-sized rash on his left eyelid at the age of 8, which slowly enlarged and progressed during the past 3 years. Physical examination revealed erythematous plaques with clear border on his face and nose. Direct microscopic examination showed slender, septate, branched hyphae. A biopsy specimen revealed mixed inflammatory infiltrations with septate hyphae noted in multinuclear giant cells. From tissue cultures, Aspergillus fumigatus was isolated and identified. The patient denied any immunosuppressive conditions, and results of routine laboratory examinations were generally normal. A CT scan excluded pulmonary aspergillosis. Therefore, the diagnosis of primary cutaneous aspergillosis was made on the basis of the above findings. The patient responds well to oral itraconazole and is still under treatment. To study the reason for the prolonged infection and identify the genetic background in this seemingly immunocompetent patient, we screened mutations in several related genes. Sanger sequencing of CARD9 showed that the patient harbored a homozygous frame shift mutation in exon 6 (c.819_820insG, p.D274fsX60), leading to premature termination codons. His son was asymptomatic and heterozygous carrier of the same mutation. CARD9, mainly expressed in myeloid cells, is a key adaptor in the downstream signaling of several C-type lectin receptors, and mediates anti-fungal immunity by forming a complex with BCL10 and MALT1. This is, to our knowledge, the first report that linked cutaneous aspergillosis to CARD9 mutations. This work enriches both the phenotypic spectrum of CARD9 deficiencies and the genetic background of primary cutaneous aspergillosis.

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