Preclinical evaluation of the ROCK1 inhibitor, GSK269962A, in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with high mortality that urgently requires new treatments. ROCK1 plays an essential role in regulating growth and survival in AML cells. In this study, we evaluated GSK269962A, a selective ROCK1 inhibitor, in preclinical models of AML. Compared with solid tumors, GSK269962A selectively inhibited cell growth and clonogenicity of AML cells. Furthermore, GSK269962A arrested AML cells in the G2 phase and induced apoptosis by regulating multiple cell cycle- and apoptosis-associated proteins. Strikingly, GSK269962A could eliminate leukemia cells from bone marrow, liver, and spleen in an animal model of AML and significantly prolong mouse survival. Mechanistically, GSK269962A could inhibit the growth of AML by blocking ROCK1/c-Raf/ERK signaling pathway. Notably, a correlation was found between the expression levels of ROCK1 protein and the sensitivity of GSK269962A in AML. These data highlight the potential role of ROCK1 as an attractive target for treating AML, as well as the potential of GSK269962A for use in clinical trials of AML.

Aberrant activation of TGF-β/ROCK1 enhances stemness during prostatic stromal hyperplasia

“…Our research affirms the effectiveness of the small molecule inhibitor GSK269962A in mitigating interstitial prostatic hyperplasia. Pan et al conducted analyses on potential cytotoxic side effects of GSK269962A in C57BL/6 mice, revealing no overt harmful effects on vital organs or the hematological system, and other study suggest that some side effects of GSK269962A were hypotension and cardiovascular collapse [ 70 , 71 ]. However, we cannot quantify the side effects of GSK269962A due to the limited experimental conditions.…”

Characterization of tumor-associated endothelial cells and the development of a prognostic model in pancreatic ductal adenocarcinoma

“…AZ628 is a RAF kinase inhibitor that suppresses MITF and FRA-1, transcription factors associated with EGFR expression, leading to inhibited cell growth and migration in V600 BRAF wild-type melanoma cells [47]. GSK269962A, a ROCK1 inhibitor, induces apoptosis in acute myeloid leukemia cells by blocking the ROCK1/c-RAF/ERK pathway [48]. Pazopanib, initially developed as a small-molecule inhibitor of vascular endothelial growth factor receptors, is a tyrosine kinase inhibitor [49].…”

Exploration of the combined role of immune checkpoints and immune cells in the diagnosis and treatment of ankylosing spondylitis: a preliminary study immune checkpoints in ankylosing spondylitis

“…As a highly selective p38 MAPK inhibitor, Doramapimod mitigates the production of inflammatory cytokines and excessive activation of inflammatory responses by inhibiting the activity of the p38 MAPK signaling pathway [51,52]. GSK269962A is a selective inhibitor of ROCK1 (Rho-associated protein kinase 1) [53]. In a mouse model of AS, the inhibition of ROCK1 and the activation of p-Erk1/2 in the MAPK signaling pathway were found to suppress the osteoblast-related classical Wnt/β-catenin pathway, thereby alleviating abnormal ossification in AS [54].…”