scholarly journals Discovery of a Potent and Highly Isoform-Selective Inhibitor of the Neglected Ribosomal Protein S6 Kinase Beta 2 (S6K2)

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5133
Author(s):  
Stefan Gerstenecker ◽  
Lisa Haarer ◽  
Martin Schröder ◽  
Mark Kudolo ◽  
Martin P. Schwalm ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Title Compound ◽  
Growth Factor Receptor ◽  
Selective Inhibitor ◽  
Nucleophilic Aromatic Substitution ◽  
Aromatic Substitution ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Beta 2 ◽  
Ribosomal Protein S6 Kinase

The ribosomal protein S6 kinase beta 2 (S6K2) is thought to play an important role in malignant cell proliferation, but is understudied compared to its closely related homolog S6 kinase beta 1 (S6K1). To better understand the biological function of S6K2, chemical probes are needed, but the high similarity between S6K2 and S6K1 makes it challenging to selectively address S6K2 with small molecules. We were able to design the first potent and highly isoform-specific S6K2 inhibitor from a known S6K1-selective inhibitor, which was merged with a covalent inhibitor engaging a cysteine located in the hinge region in the fibroblast growth factor receptor kinase (FGFR) 4 via a nucleophilic aromatic substitution (SNAr) reaction. The title compound shows a high selectivity over kinases with an equivalently positioned cysteine, as well as in a larger kinase panel. A good stability towards glutathione and Nα-acetyl lysine indicates a non-promiscuous reactivity pattern. Thus, the title compound represents an important step towards a high-quality chemical probe to study S6K2-specific signaling.

scholarly journals Discovery of a Potent and Highly Isoform-Selective Inhibitor of the Neglected Ribosomal Protein S6 Kinase Beta 2 (S6K2)

2021 ◽  
Author(s):  
Stefan Gerstenecker ◽  
Lisa Haarer ◽  
Martin Schröder ◽  
Mark Kudolo ◽  
Martin P. Schwalm ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Selective Inhibitor ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Beta 2 ◽  
Ribosomal Protein S6 Kinase

scholarly journals pS6K1 as an efficacy marker of GnRH agonist with premenopausal breast cancer

2019 ◽  
Vol 8 (7) ◽  
pp. 863-869
Author(s):  
Chan Sub Park ◽  
Jihye Choi ◽  
Min-Ki Seong ◽  
Sung-Eun Hong ◽  
Jae-Sung Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ribosomal Protein ◽  
Growth Factor Receptor ◽  
Gonadotropin Releasing Hormone ◽  
S6 Kinase ◽  
Releasing Hormone ◽  
Gonadotropin Releasing Hormone Agonist ◽  
Ribosomal Protein S6 ◽  
Epidermal Growth ◽  
Ribosomal Protein S6 Kinase

Estradiol is a key factor for tumorigenesis and prognosis of hormone receptor-positive breast cancer. Adipocytes are one source of estradiol in patients with breast cancer. Recent studies have shown that phosphorylated ribosomal protein S6 kinase-1 plays a critical role in adipogenesis. Therefore, estrogen depletion therapy might have beneficial effects in phosphorylated ribosomal protein S6 kinase-1-positive breast cancer. This study was conducted to evaluate the value of phosphorylated ribosomal protein S6 kinase-1 as a marker for gonadotropin-releasing hormone agonist treatment, a form of estrogen depletion therapy, for premenopausal patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer. We reviewed the medical records of 296 premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary invasive breast cancer treated between 2008 and 2015. Phosphorylated ribosomal protein S6 kinase-1 positivity was defined by immunohistochemical staining scores of 1+, 2+ and 3+, whereas a score of 0 was considered negative. Phosphorylated ribosomal protein S6 kinase-1-positive tumors were found in 74.0% of the patients. In the phosphorylated ribosomal protein S6 kinase-1-positive group, disease-free survival of patients treated with a gonadotropin-releasing hormone agonist was significantly longer than that of patients treated without a gonadotropin-releasing hormone agonist (mean 106.7 months vs mean 91.1 months, P = 0.018). Phosphorylated ribosomal protein S6 kinase-1 is a potential biomarker for predicting the efficacy of gonadotropin-releasing hormone agonist therapy in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.

The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-α in 3T3-L1 adipocytes and is a target for transactivation by PPARγ

2006 ◽  
Vol 291 (1) ◽  
pp. E115-E127 ◽  
Author(s):  
Ji Young Kim ◽  
Kristin Tillison ◽  
Jun-Ho Lee ◽  
David A. Rearick ◽  
Cynthia M. Smas
Keyword(s):  
Adipose Tissue ◽  
Ribosomal Protein ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
S6 Kinase ◽  
Triglyceride Lipase ◽  
Ribosomal Protein S6 ◽  
Tnf Α ◽  
Adipose Tissue Triglyceride ◽  
Ribosomal Protein S6 Kinase

The minimal adipose phenotype of hormone-sensitive lipase (HSL)-null mice suggested that other hormonally responsive lipase(s) were present in adipocytes. Recent studies have characterized a new adipose tissue triglyceride lipase, ATGL/PNPLA2/destnutrin/iPLA2ζ/TTS2.2 (ATGL). We had previously cloned a novel adipose-enriched transcript by differential screening and recently determined its identity with murine ATGL. We report here on the regulation of ATGL by TNF-α and insulin in 3T3-L1 adipocytes and identify ATGL as a target for transcriptional activation by the key adipogenic transcription factor PPARγ. Insulin at 100 nM resulted in a marked decrease in ATGL transcript that was effectively blocked by inhibitors for PI 3-kinase and p70 ribosomal protein S6 kinase. TNF-α treatment decreased ATGL transcript in a time-dependent manner that paralleled TNF-α downregulation of PPARγ with a maximal decrease noted by 6 h. TNF-α effects on ATGL were attenuated by pretreatment with PD-98059, LY-294002, or rapamycin, suggesting involvement of the p44/42 MAP kinase, PI 3-kinase, and p70 ribosomal protein S6 kinase signals. To study transcriptional regulation of ATGL, we cloned 2,979 bp of the murine ATGL 5′-flanking region. Compared with promoterless pGL2-Basic, the −2979/+21 ATGL luciferase construct demonstrated 120- and 40-fold increases in activity in white and brown adipocytes, respectively. Luciferase reporter activities for a series of eight ATGL promoter deletions revealed that the −928/+21, −1738/+21, −1979/+21, and −2979/+21 constructs were transactivated by PPARγ. Our findings identify the novel lipase ATGL to be a target gene for TNF-α and insulin action in adipocytes and reveal that it is subject to transcriptional control by PPARγ-mediated signals.

Sign in / Sign up

Export Citation Format

Share Document