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ROCK2 interacts with and phosphorylates STAT3, leading to the formation of the JAK2-STAT3 complex and the upregulation of
Th17 and Tfh cells.2,4,5
Thymic injury induced by high-dose chemotherapy and irradiation during a BMT inhibits the production of Treg cells and allows autoreactive and alloreactive T cells to escape regulation and contribute to chronic inflammation.6,7
Decreases activation of STAT3, triggering the significant downregulation of both Th17 and Tfh cells, leading to the downregulation of pro-inflammatory cytokines.2,5
Increases phosphorylation of STAT5,
causing the upregulation of Treg cells.4 This has an immunomodulatory effect on STAT3 and STAT5 phosphorylation that reduces inflammation.2,5
Macrophages activate profibrotic mediators, such as LPA and TGF-β, to subsequently activate ROCK2,8,9 which polymerizes G-actin to F-actin.8 This frees the transcription factor MRTF and leads to transcription of profibrotic genes.8
The process results in
changes to the cellular structure, increasing tissue stiffness.8
Prevents the polymerization of G-actin to F-actin, as well as MRTF changes to profibrotic gene expression.8
Downregulates fibrosis, as evidenced by decreased collagen deposition around the bronchioles and the delayed progression of scleroderma in animal cGVHD models.3
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ROCK2 interacts with and phosphorylates STAT3, leading to the formation of the JAK2-STAT3 complex and the upregulation of Th17 and Tfh cells.2,4,5
Decreases activation of STAT3, triggering the significant downregulation of both Th17 and
Tfh cells.2,5
Thymic injury induced by high-dose chemotherapy and irradiation during a BMT inhibits the production of Treg cells and allows autoreactive and alloreactive T cells to escape regulation and contribute to chronic inflammation.6,7
Increases phosphorylation of STAT5, causing the upregulation of Treg cells.4 This has an immunomodulatory effect on STAT3 and STAT5 phosphorylation that reduces inflammation.2,5
Macrophages activate profibrotic mediators, such as LPA and thrombin, to subsequently activate ROCK2,8,9 which polymerizes G-actin to F-actin.8 This frees the transcription factor MRTF and leads to transcription of profibrotic genes.8
Prevents the polymerization of G-actin to F-actin, as well as MRTF changes to profibrotic gene expression.8
The process results in changes to the cellular structure, increasing tissue stiffness.8
Downregulates fibrosis, as evidenced by decreased collagen deposition around the bronchioles and the delayed progression of scleroderma in animal cGVHD models.3
REZUROCK is an effective and innovative treatment designed to restore immune homeostasis and to downregulate the fibrotic processes of cGVHD.1-3
BMT, bone marrow transplant; cGVHD, chronic graft-versus-host disease; JAK2, Janus-associated kinase 2; LPA, lysophosphatidic acid; MOA, mechanism of action; MRTF, myocardin-related transcription factor; ROCK2, rho-associated coiled-coil–containing protein kinase-2; STAT3, signal transducer and activator of transcription factor 3; STAT5, signal transducer and activator of transcription factor 5; Tfh, follicular helper T [cell]; TGF-B, transforming growth factor-beta; Th17, type 17 helper T [cell], Treg, regulatory T [cell].
References: 1. REZUROCK. Package insert. Kadmon Pharmaceuticals, LLC; 2021. 2. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci USA. 2014;111(47):16814-16819. doi:10.1073/pnas.1414189111 3. Flynn R, Paz K, Du J, et al. Targeted rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127(17):2144-2154. doi:10.1182/blood-2015-10-678706 4. Chen W, Nyuydzefe MS, Weiss JM, Zhang J, Waksal SD, Zanin-Zhorov A. ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells. Sci Rep. 2018;8(1):16636. doi:10.1038/s41598-018-35109-9 5. Weiss JM, Chen W, Nyuydzefe MS, et al. ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings. Sci Signal. 2016;9(437):ra73. doi:10.1126/scisignal.aad8953 6. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565-2579. doi:10.1056/NEJMra1703472 7. Matsuoka K-I, Kim HT, McDonough S, et al. Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2010;120(5):1479-1493. doi:10.1172/JC141072 8. Riches DWH, Backos DS, Redente EF. ROCK and Rho: promising therapeutic targets to ameliorate pulmonary fibrosis. Am J Pathol. 2015;185(4):909-912. doi:10.1016/j.ajpath.2015.01.005
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