Belumosudil | ROCK2 Inhibitor

Belumosudil (911417-87-3) is a selective inhibitor of Rho kinase 2 (ROCK2) – IC₅₀’s: ROCK2 = 105 nM, ROCK1 = 24 µM in enzyme assays.¹ It downregulated the ability of T cells to secrete IL-21 and IL-17, but not IFN-g, in response to T cell stimulation in vitro via a STAT3-dependent mechanism.² Belumosudil ameliorated graft-versus-host disease in multiple models^3,4 and was recently approved by the FDA for the treatment of GVHD (July 2021). It has also been shown to suppress adipogenesis.^5-7 Suppression of adipocyte differentiation is mediated via casein kinase 2 inhibition (IC₅₀ = 50 nM) and not ROCK2 inhibition.⁸

References:

1. Boerma et al. (2008) Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin; Blood Coagul. Fibrinolysis. 19 709
2. Zanin-Zhorov et al. (2014) Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism; Natl. Acad. Sci. USA 111 16814
3. Flynn et al. (2016) Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism; 127 2144
4. Jagasia et al. (2021) ROCK2 Inhibition with Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease; Clin. Invest. 39 1888
5. Diep et al. (2018) Anti-adipogenic effects of KD025 (SLx-2119), a ROCK2-specific inhibitor, in 3T3-L1 cells; Rep. 8 2477
6. Diep et al. (2019) KD025 (SLx-2119) suppresses adipogenesis at intermediate stage in human adipose-derived stem cells; Adipocyte 9 114
7. Wei et al. (2020) ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice; FASEB J. 34 474
8. Tran and Chun (2021) ROCK2-Specific Inhibitor KD025 Suppresses Adipocyte Differentiation by Inhibiting Casein Kinase 2; Molecules 26 4747