A visible light-controllable Rho kinase inhibitor based on a photochromic phenylazothiazole

2021 ◽  
Author(s):  
Kazuya Matsuo ◽  
Sampreeth Thayyil ◽  
Mitsuyasu Kawaguchi ◽  
Hidehiko Nakagawa ◽  
Nobuyuki Tamaoki
Keyword(s):  
Protein Kinase ◽  
Visible Light ◽  
Kinase Inhibitor ◽  
Coiled Coil ◽  
Rho Kinase ◽  
Rock Inhibitor ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Rho Kinase Inhibitor

Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine-threonine kinase, whose inhibitors are useful for the regulation of actomyosin system. Here, we developed a photoswitchable ROCK inhibitor based on a phenylazothiazole...

Animal model for angiotensin II effects in the internal anal sphincter smooth muscle: mechanism of action

2002 ◽  
Vol 282 (3) ◽  
pp. G461-G469 ◽  
Author(s):  
Ya-Ping Fan ◽  
Rajinder N. Puri ◽  
Satish Rattan
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Ang Ii ◽  
Kinase C ◽  
Rho Kinase Inhibitor ◽  
Isolated Smooth Muscle Cells

Effect of ANG II was investigated in in vitro smooth muscle strips and in isolated smooth muscle cells (SMC). Among different species, rat internal and sphincter (IAS) smooth muscle showed significant and reproducible contraction that remained unmodified by different neurohumoral inhibitors. The AT1antagonist losartan but not AT2 antagonist PD-123319 antagonized ANG II-induced contraction of the IAS smooth muscle and SMC. ANG II-induced contraction of rat IAS smooth muscle and SMC was attenuated by tyrosine kinase inhibitors genistein and tyrphostin, protein kinase C (PKC) inhibitor H-7, Ca2+ channel blocker nicardipine, Rho kinase inhibitor Y-27632 or p44/42mitogen-activating protein kinase (MAPK44/42) inhibitor PD-98059. Combinations of nicardipine and H-7, Y-27632, and PD-98059 caused further attenuation of the ANG II effects. Western blot analyses revealed the presence of both AT1 and AT2receptors. We conclude that ANG II causes contraction of rat IAS smooth muscle by the activation of AT1 receptors at the SMC and involves multiple intracellular pathways, influx of Ca2+, and activation of PKC, Rho kinase, and MAPK44/42.

scholarly journals Effectiveness of Ripasudil, a Rho-Associated Coiled/Coil-Containing Protein Kinase Inhibitor, in Improving Retinoschisis and Cystic-Like Foveal Cavities in Eyes with X-Linked Retinoschisis

2020 ◽  
Vol 11 (2) ◽  
pp. 411-417
Author(s):  
Hitomi Suimon ◽  
Masahiko Sugimoto ◽  
Hisashi Matsubara ◽  
Mineo Kondo
Keyword(s):  
Protein Kinase ◽  
Chart Review ◽  
Kinase Inhibitor ◽  
Coiled Coil ◽  
Clinical Information ◽  
Rock Inhibitor ◽  
First Case ◽  
Juvenile Retinoschisis ◽  
Successful Resolution ◽  
Visual Disturbances

This is the first reported case of a successful resolution of cystic-like foveal cavities in eyes with X-linked juvenile retinoschisis (XLRS) treated with topical ripasudil hydrochloride hydrate, a Rho-associated coiled/coil-containing protein kinase (ROCK) inhibitor. A chart review was performed on 1 patient to collect all relevant clinical information and the optical coherence tomographic (OCT) images. A healthy 18-year-old young man presented with bilateral visual disturbances. The patient was diagnosed with XLRS from the spoke-wheel pattern around the macula, negative electroretinograms, and retinoschisis with cystic-like foveal cavities in the OCT images. Significant reductions of the retinoschisis and cystic-like cavities were observed after treatment with topical ripasudil. This is the first case of XLRS that had a resolution of cystic-like foveal cavities after topical ripasudil, a ROCK inhibitor. Since many XLRS patients have a worsening of their visual acuities due to the progressive nature of retinoschisis and cystic-like foveal cavities, topical ripasudil offers a potential treatment option.

scholarly journals A promiscuous kinase inhibitor delineates the conspicuous structural features of protein kinase CK2a1

2019 ◽  
Vol 75 (7) ◽  
pp. 515-519
Author(s):  
Masato Tsuyuguchi ◽  
Tetsuko Nakaniwa ◽  
Masaaki Sawa ◽  
Isao Nakanishi ◽  
Takayoshi Kinoshita
Keyword(s):  
Crystal Structure ◽  
Protein Kinase ◽  
Crystal Structures ◽  
Crucial Role ◽  
Kinase Inhibitor ◽  
Structural Features ◽  
Kinase Domain ◽  
Selective Inhibitors ◽  
Serine Threonine Kinase ◽  
Threonine Kinase

Protein kinase CK2a1 is a serine/threonine kinase that plays a crucial role in the growth, proliferation and survival of cells and is a well known target for tumour and glomerulonephritis therapies. Here, the crystal structure of the kinase domain of CK2a1 complexed with 5-iodotubercidin (5IOD), an ATP-mimetic inhibitor, was determined at 1.78 Å resolution. The structure shows distinct structural features and, in combination with a comparison of the crystal structures of five off-target kinases complexed with 5IOD, provides valuable information for the development of highly selective inhibitors.

Inhibition of protein kinase C-mediated contraction by Rho kinase inhibitor fasudil in rabbit aorta

2004 ◽  
Vol 370 (5) ◽  
pp. 414-422 ◽  
Author(s):  
Erika Shimomura ◽  
Mitsuya Shiraishi ◽  
Takahiro Iwanaga ◽  
Minoru Seto ◽  
Yasuharu Sasaki ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Rabbit Aorta ◽  
Kinase C ◽  
Rho Kinase Inhibitor

scholarly journals Renal ROCK Activation and Its Pharmacological Inhibition in Patients With Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Keiichiro Matoba ◽  
Kensuke Sekiguchi ◽  
Yosuke Nagai ◽  
Yusuke Takeda ◽  
Hiroshi Takahashi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Body Height ◽  
Coiled Coil ◽  
Renal Outcome ◽  
Rock Inhibitor ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Patients With Diabetes ◽  
Rock Activity

Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine/threonine kinase with essential roles in cytoskeletal functions. Substantial evidence implicates ROCK as a critical regulator in the inception and progression of diabetic nephropathy through a mechanism involving mesangial fibrosis, podocyte apoptosis, and endothelial inflammation. Despite these experimental observations, human data is lacking. Here we show that the phosphorylated form of myosin phosphatase targeting subunit 1 (MYPT1), a ROCK substrate, was increased in both the glomerular and tubulointerstitial areas in patients with histologically confirmed diabetic nephropathy. We also conducted a retrospective pilot analysis of data from patients with diabetes to assess the renoprotective effects of fasudil, an ATP-competitive ROCK inhibitor licensed in Japan for the prevention of vasospasm following subarachnoid hemorrhage. Fifteen subjects (male, n = 8; female, n = 7; age 65.7 ± 14.7 years; body height, 161.1 ± 12.6 cm; body weight, 57.6 ± 13.7 kg; body mass index, 22.4 ± 3.7 kg/m2) were enrolled to evaluate blood pressure and the renal outcome after fasudil treatment. Of note, proteinuria was significantly reduced at the end of the fasudil treatment without affecting the blood pressure or estimated glomerular filtration rate. Taken together, these findings suggest that the administration of fasudil could be associated with a better renal outcome by inhibiting the ROCK activity in patients with diabetes.

Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer

2008 ◽  
Vol 26 (7) ◽  
pp. 1135-1141 ◽  
Author(s):  
Yun Oh ◽  
Roy S. Herbst ◽  
Howard Burris ◽  
Ann Cleverly ◽  
Luna Musib ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Small Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Stage Iv ◽  
Small Cell ◽  
Small Cell Lung ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Grade 3

PurposeEnzastaurin, an oral serine/threonine kinase inhibitor, suppresses protein kinase C (PKC) and protein kinase B/AK transforming (AKT) signaling, induces tumor cell apoptosis, and inhibits proliferation and angiogenesis. Increased PKC and AKT activity is associated with poor prognosis in non–small-cell lung cancer (NSCLC). This phase II trial of enzastaurin was conducted to determine the 6-month progression-free survival (PFS) rate in advanced, metastatic NSCLC.Patients and MethodsPatients with metastatic (stage IV and wet IIIB) NSCLC, Eastern Cooperative Oncology Group performance status ≤ 2, and ≤ two prior systemic regimens (including one or more platinum-based chemotherapy regimens) received 500 mg of enzastaurin administered once daily.ResultsFifty-five patients were enrolled (55% male patients, 45% female patients; median age, 63 years; range, 44 to 82 years; 78% of patients having stage IV disease). Adenocarcinoma was the most common diagnosis (65%). Prior therapies included radiotherapy (73%) and epidermal growth factor inhibitors (29%). Median PFS was 1.8 months (95% CI, 1.7 to 1.9). Six-month PFS rate was 13% (95% CI, 3.9% to 21.5%). Median overall survival (OS) was 8.4 months (95% CI, 6.0 to 13.6 months). The 12-month OS rate was 44% (95% CI, 30.5% to 57.3%). Nineteen patients (35%) had stable disease. No objective responses were observed. Seven patients (13%) had PFS ≥ 6 months, three of whom continued for more than 10 months. The most common toxicity was fatigue (grade ≤ 3; n = 17). Grade 3 or worse toxicities were fatigue (n = 2), thromboembolism (n = 1), ataxia (n = 1), and anemia (n = 1). Two patients discontinued treatment because of drug-related fatigue and dizziness. Five patients died while enrolled in the study (non drug-related).ConclusionAlthough the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for ≥ 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.

scholarly journals FSD-C10: A more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity

2015 ◽  
Vol 35 (5) ◽  
Author(s):  
Yan-Le Xin ◽  
Jie-Zhong Yu ◽  
Xin-Wang Yang ◽  
Chun-Yun Liu ◽  
Yan-Hua Li ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Rho Kinase ◽  
Rock Inhibitor ◽  
Rho Kinase Inhibitor ◽  
Cns Autoimmunity ◽  
Low Cytotoxicity

Compared with Fasudil, novel Rho kinase inhibitor FSD-C1 exhibited similar therapeutic potential and mechanisms in EAE, but had low cytotoxicity and vasodilation, providing a more promising novel ROCK inhibitor for the treatment of several neurological disorders.

scholarly journals Structural Analysis of Protein Kinase A Mutants with Rho-kinase Inhibitor Specificity

2006 ◽  
Vol 281 (34) ◽  
pp. 24818-24830 ◽  
Author(s):  
Stefan Bonn ◽  
Saturnino Herrero ◽  
Christine B. Breitenlechner ◽  
Andrea Erlbruch ◽  
Wolf Lehmann ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Inhibitor Specificity ◽  
Rho Kinase Inhibitor ◽  
Kinase A
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