The HSP90 inhibitor RGRN‐305 exhibits strong immunomodulatory effects in human keratinocytes

Abstract

Keratinocytes are the key cellular target for IL‐17A‐mediated effects in psoriasis and HSP90 is important for IL‐17A‐mediated signalling. RGRN‐305 is a novel HSP90 inhibitor reported to reduce psoriatic phenotypes in preclinical animal models. The aim of this study was to investigate the effect of RGRN‐305 on a psoriasis‐like inflammatory response in human keratinocytes in vitro. Using RT‐qPCR, we demonstrated a significantly increased expression of the HSP90 isoforms HSP90AB1, HSP90B1 and TRAP1 in lesional compared with non‐lesional psoriatic skin. In a psoriasis‐like setting where keratinocytes were stimulated with TNFα and/or IL‐17A, we analysed the mRNA expression using the NanoString nCounter technology and demonstrated that the HSP90 inhibitor RGRN‐305 significantly reduced the IL‐17A‐ and TNFα‐induced gene expression of a number of proinflammatory genes, including the psoriasis‐associated genes CCL20, NFKBIZ, IL36G and IL23A. In agreement with the mRNA data, the protein level of CCL20, IκBζ and IL‐36γ were inhibited by RGRN‐305 as demonstrated by western blotting and ELISA. Interestingly, when keratinocytes were stimulated with a TLR3 agonist, RGRN‐305 also demonstrated potent immunomodulatory effects, significantly inhibiting poly(I:C)‐induced expression of the proinflammatory genes TNFα, IL1B, IL6 and IL23A. Taken together, our data support a role for HSP90 not only in the pathogenesis of psoriasis, but also in broader immune responses. Therefore, HSP90 provides an attractive target for the treatment of psoriasis and other diseases where the innate immune system plays an important role.

HSP90 inhibitor RGRN‐305 for oral treatment of plaque‐type psoriasis: efficacy, safety and biomarker results in an open‐label proof‐of‐concept study*

“…43 This inactivation of HSP90 leads to inhibition of the expression of multiple proinflammatory cytokines and chemokines, as recently shown in cultured normal human keratinocytes in vitro, where cells stimulated with either IL-17A and TNF-a or the Toll-like receptor 3 agonist poly(I:C) showed reduced expression of a number of proinflammatory genes such as CCL20, IL36G, IL23A, TNF-a, IL1B and IL6. 18 This is consistent with findings from the present study where treatment with RGRN-305 normalized the gene expression signature in psoriasis lesions in the responder group over the 12week treatment period.…”

“…[15][16][17] HSP90 is also known as a downstream regulator of IL-17A signalling. 14,18 Human psoriatic lesions display increased expression of HSP90 compared with nonlesional skin and normal skin, which is thought to be partially associated with IL-17-induced inflammation. 16,19 In addition, HSP90 is also employed in Janus kinase/signal transduction and activator of transcription (JAK/ STAT) signalling.…”

Key Signaling Pathways in Psoriasis: Recent Insights from Antipsoriatic Therapeutics

“…The HSP90 inhibitor RGRN-305 has shown promising antipsoriatic effects in a xenograft mouse model, and in vitro it inhibited the expression of proinflammatory genes such as TNFα, IL23A and NFKBIZ (encoding IκBζ) in cultured normal human keratinocytes. 125 , 126 A Phase 1 clinical trial with RGRN-305 in patients with psoriasis is currently ongoing (NCT03675542).…”

Recent progress at the psoriasis and atopic dermatitis research front: An experimental dermatology perspective

“…In the current issue, Hansen et al 11 . found that RGRN‐305, a novel HSP90 inhibitor, potently suppress TNF, IL‐17A and/or poly(I:C)‐mediated proinflammatory responses in cultured keratinocytes.…”

“…We also include new EXD studies related to allergic contact dermatitis (ACD), because it shares similar signs and symptoms as AD, including pruritus, along with burning and stinging 8 . In this Editorial, these recent EXD papers are briefly highlighted and placed into the context of the current literature, including four articles in the current issue 9‐12 . With this exercise, the Editors hope to synthesize exemplarily where translational immunopathology research in these key areas of experimental dermatology is headed, and which challenges and open questions remain.…”