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<p>Interleukin-1 receptor associated kinase (IRAK)1 and IRAK4 are serine/threonine kinases critical for downstream signaling of most toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs), leading to proinflammatory cytokine production and activation of innate immune and inflammatory responses. Herein, we describe the preclinical characterization and early clinical development of R835, a potent, selective dual inhibitor of IRAK1/IRAK4 and the active metabolite of the prodrug R289, which is currently undergoing clinical evaluation in relapsed/refractory lower-risk myelodysplastic syndrome (LR-MDS). In multiple cell types and in orally dosed mice, R835 potently and selectively inhibited TLR- and IL-1R-dependent proinflammatory cytokine production. In a randomized, placebo-controlled, double-blind, phase 1, first-in-human study in 82 healthy participants, R835 was well tolerated with a favorable pharmacokinetic profile and markedly inhibited lipopolysaccharide-induced cytokine release (TNF, IL-6, IL-8, MIP1α, and MIP1β) compared with placebo, mirroring preclinical data. Taken together, these initial findings indicate that R835 may represent a novel therapeutic for inflammatory diseases.</p>

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Preclinical characterization and early development of R835, a novel, selective dual IRAK1 and IRAK4 inhibitor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Simon J. Shaw,
  • Chrystelle Lamagna,
  • Vadim Markovtsov,
  • Toufigh Gordi,
  • Lucy Yan,
  • Sylvia Braselmann,
  • Esteban S. Masuda,
  • Vanessa Taylor

摘要

Interleukin-1 receptor associated kinase (IRAK)1 and IRAK4 are serine/threonine kinases critical for downstream signaling of most toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs), leading to proinflammatory cytokine production and activation of innate immune and inflammatory responses. Herein, we describe the preclinical characterization and early clinical development of R835, a potent, selective dual inhibitor of IRAK1/IRAK4 and the active metabolite of the prodrug R289, which is currently undergoing clinical evaluation in relapsed/refractory lower-risk myelodysplastic syndrome (LR-MDS). In multiple cell types and in orally dosed mice, R835 potently and selectively inhibited TLR- and IL-1R-dependent proinflammatory cytokine production. In a randomized, placebo-controlled, double-blind, phase 1, first-in-human study in 82 healthy participants, R835 was well tolerated with a favorable pharmacokinetic profile and markedly inhibited lipopolysaccharide-induced cytokine release (TNF, IL-6, IL-8, MIP1α, and MIP1β) compared with placebo, mirroring preclinical data. Taken together, these initial findings indicate that R835 may represent a novel therapeutic for inflammatory diseases.