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- W4366186064 abstract "TRPV3 is a warm temperature-sensitive cation channel, abundantly expressed in skin, with high permeability to Ca+2. Its activation results in induction of skin differentiation and hyperkeratosis accompanied by increased inflammation. Gain-of-function mutation of TRPV3, is the cause of Olmsted syndrome and its epidermal overexpression is seen in several types of Keratodermas such as Pachyonychia congenita. Kamari Pharma has developed potent and specific TRPV3 inhibitors. KM-001 is a clinical stage drug candidate that inhibits TRPV3 with an IC50 of ∼3nM. It also significantly reduces Ca+2flux in keratinocytes and normalizes differentiation markers including filaggrin, involucrin, and keratin-1 (100-500 nM). TRPV3 forms a signaling complex with EGFR, resulting in increased TRPV3 activity and stimulation of downstream secondary messengers. In nHEK induced by EGF or transfected with mutated TRPV3, KM-001 significantly decreased the level of EGFR phosphorylation and its downstream target Ribosomal Protein S6. Furthermore, KM-001 significantly reduced the expression and secretion of IL-6 and TSLP in keratinocytes activated by proinflammatory cytokines. KM-001 was tested in DS-Nh mice that develop dermatitis, hyperkeratosis and pruritus, resulting from a ‘gain-of-function’ TRPV3 mutation. Mice treated with topical KM-001 1% for 14 days showed 88% reduction in scratching in comparison to the vehicle control and demonstrated marked improvement in skin histology, with 70% of mice treated with KM-001 exhibiting skin normalization. KM-001 demonstrated a favorable topical and systemic non-mutagenic safety profile in rodents and minipigs. Several Clinical trials with topical KM-001, are ongoing in patients with keratoderma and itch and may be new promising therapies for treatment of diseases with unmet need." @default.
- W4366186064 created "2023-04-19" @default.
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- W4366186064 date "2023-05-01" @default.
- W4366186064 modified "2023-09-28" @default.
- W4366186064 title "1104 Novel and selective TRPV3 inhibitors as new potential treatments for keratodermas and itch" @default.
- W4366186064 doi "https://doi.org/10.1016/j.jid.2023.03.1116" @default.
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