부산대학교 도서관

Simple Summary: Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow with high relapse rates. Standard AML treatment has evolved to yield more frequent remission for patients, with little effect on the disease's low five-year survival rate. Patients exhibit a wide variation of molecular alterations, driving efforts to profile patients based on these genetic mutations. Previously, our group developed a novel Rho-associated protein kinase (ROCK) inhibitor, DJ4, and biochemical analysis demonstrated its potency in human cancer cell lines. This work targets the overactive ROCKs, which will help patients that experience abnormalities with ROCK-related processes that have been correlated to various cancers. We provide evidence to support the therapeutic efficacy of DJ4 and indicate its promise to improve AML therapy. Our results indicate that inhibiting ROCK makes AML cells susceptible to cell death and, in leukemia mouse models, reduces disease progression and enhances survival. The poor prognosis of acute myeloid leukemia (AML) and the highly heterogenous nature of the disease motivates targeted gene therapeutic investigations. Rho-associated protein kinases (ROCKs) are crucial for various actin cytoskeletal changes, which have established malignant consequences in various cancers, yet are still not being successfully utilized clinically towards cancer treatment. This work establishes the therapeutic activity of ROCK inhibitor (5Z)-2–5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)-1,3-thiazol-4(5H)-one (DJ4) in both in vitro and in vivo preclinical models of AML to highlight the potential of this class of inhibitors. Herein, DJ4 induced cytotoxic and proapoptotic effects in a dose-dependent manner in human AML cell lines (IC50: 0.05–1.68 μM) and primary patient cells (IC50: 0.264–13.43 μM); however, normal hematopoietic cells were largely spared. ROCK inhibition by DJ4 disrupts the phosphorylation of downstream targets, myosin light chain (MLC2) and myosin-binding subunit of MLC phosphatase (MYPT), yielding a potent yet selective treatment response at micromolar concentrations, from 0.02 to 1 μM. Murine models injected with luciferase-expressing leukemia cell lines subcutaneously or intravenously and treated with DJ4 exhibited an increase in overall survival and reduction in disease progression relative to the vehicle-treated control mice. Overall, DJ4 is a promising candidate to utilize in future investigations to advance the current AML therapy. [ABSTRACT FROM AUTHOR]