Article
Multidisciplinary Sciences
Tadatoshi Sato, Christian D. Castro Andrade, Sung-Hee Yoon, Yingshe Zhao, William J. Greenlee, Patricia C. Weber, Usha Viswanathan, John Kulp, Daniel J. Brooks, Marie B. Demay, Mary L. Bouxsein, Bruce Mitlak, Beate Lanske, Marc N. Wein
Summary: This study identifies SIK2/SIK3 as potential drug targets for treating osteoporosis and successfully develops an orally available SIK2/SIK3 inhibitor. The inhibitor stimulates bone formation and increases bone density without apparent toxicity. These findings provide a new approach for the pharmacological treatment of osteoporosis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Hadla Hariri, Rene St-Arnaud
Summary: This review highlights recent research on the regulatory functions of ubiquitin-specific peptidases (USPs) in osteoblasts and provides insight into the molecular mechanisms governing their actions. It also discusses the role of USP53 in osteoblasts and the complex layers of regulation exerted by USPs on osteoblast signaling. Further studies using knockout mouse models are necessary for a full understanding of the mechanisms underpinning USPs actions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Kathryn Balmanno, Andrew M. Kidger, Dominic P. Byrne, Matthew J. Sale, Nejma Nassman, Patrick A. Eyers, Simon J. Cook
Summary: Innate or acquired resistance to BRAF or MEK1/2 inhibitors often results in sustained or reinstated activation of ERK1/2. To overcome this, ERK1/2 inhibitors have been developed that can inhibit catalytic activity or prevent activation of ERK1/2. In this study, it was found that multiple ERK inhibitors can drive turnover of ERK2, the most abundant isoform, without affecting ERK1. This turnover is caused by ERKi binding to ERK2 and can be prevented by MEKi pre-treatment. ERKi treatment leads to ubiquitination and proteasome-dependent degradation of ERK2. These findings suggest that ERKi act as "kinase degraders" and may have implications for the therapeutic use of ERKi.
BIOCHEMICAL JOURNAL
(2023)
Article
Chemistry, Medicinal
Seyed-Omar Zaraei, Nour N. Al-Ach, Hanan S. Anbar, Randa El-Gamal, Hamadeh Tarazi, Rimas T. Tokatly, Rawan R. Kalla, Mouna A. Munther, Marwa M. Wahba, Aya M. Alshihabi, Mahmoud K. Shehata, Rawan M. Sbenati, Afnan I. Shahin, Raafat El-Awady, Taleb H. Al-Tel, Mohammed I. El-Gamal
Summary: This article presents the design, synthesis, and biological screening results of a new series of diarylurea and diarylamide derivatives with a quinoline core armed with dimethylamino or morpholino side chains. The compounds showed broad-spectrum antiproliferative activity against a panel of 60 cancer cell lines, with three of them demonstrating higher potency than the reference drug, sorafenib. The compounds also exhibited high selectivity for C-RAF kinase, making them potential inhibitors for this molecular target.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Plant Sciences
Nan Chen, Na-Ni Wang, Chen Du, Jia-Li Zhang, Yi-Xun Guo, Yan Zhang
Summary: Fructus Ligustri Lucidi (FLL) plays a role in mediating calcium homeostasis by stimulating renal calcium reabsorption. Salidroside and oleuropein are major ingredients in FLL that contribute to its anti-hypercalciuria effects by acting on kidney signaling pathways.
Article
Biochemistry & Molecular Biology
Hyun Ji Kim, Jung Woo Park, Sangjae Seo, Kwang-Hwi Cho, Mohammed M. Alanazi, Eun-Kyoung Bang, Gyochang Keum, Ashraf K. El-Damasy
Summary: The development of resistance to targeted therapy in cancer is a major challenge in cancer treatment. This study aimed to identify new anticancer candidates, especially those targeting oncogenic mutants. Through structural modifications, a series of tailored quinoline-based arylamides were synthesized and evaluated for their inhibitory potency against B-RAF and C-RAF kinases. Compound 17b emerged as the most potent and exhibited significant inhibitory activity against resistant B-RAF mutants. Molecular docking and molecular dynamics studies provided insights into the binding mode of 17b. Additionally, all target compounds showed superior anticancer activity compared to the lead compound in cell lines. Compound 17b demonstrated highly potent antiproliferative activity against melanoma cell lines. Therefore, 17b has the potential to be a valuable candidate for anticancer chemotherapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Endocrinology & Metabolism
Xu Feng, Ye Xiao, Qi Guo, Hui Peng, Hai-Yan Zhou, Jian-Ping Wang, Zhu-Ying Xia
Summary: Intermittent administration of PTH has been found to ameliorate non-alcoholic liver steatosis, potentially through inhibiting lipid accumulation and promoting lipid beta-oxidation.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biology
Tsz Long Chu, Peikai Chen, Anna Xiaodan Yu, Mingpeng Kong, Zhijia Tan, Kwok Yeung Tsang, Zhongjun Zhou, Kathryn Song Eng Cheah
Summary: This study reveals that MMP14 plays a crucial role in the regulation of PTH signaling, thus contributing to bone homeostasis. During the development of osteoblasts from HC-descendent cells, MMP14 and the PTH pathway are activated. MMP14 cleaves PTH1R to dampen PTH signaling, thereby regulating bone synthesis.
Article
Cell Biology
Avinashnarayan Venkatanarayan, Jason Liang, Ivana Yen, Frances Shanahan, Benjamin Haley, Lilian Phu, Erik Verschueren, Trent B. Hinkle, David Kan, Ehud Segal, Jason E. Long, Tony Lima, Nicholas P. D. Liau, Jawahar Sudhamsu, Jason Li, Christiaan Klijn, Robert Piskol, Melissa R. Junttila, Andrey S. Shaw, Mark Merchant, Matthew T. Chang, Donald S. Kirkpatrick, Shiva Malek
Summary: CRAF is necessary for the growth of KRAS mutant tumors and its dimerization plays a vital role. Lack of CRAF leads to sustained ERK activation and cell cycle arrest, and the CRAF-loss phenotype can be rescued by inhibiting MEK or ERK.
Article
Endocrinology & Metabolism
Emilia Przygrodzka, Xiaoying Hou, Pan Zhang, Michele R. Plewes, Rodrigo Franco, John S. Davis
Summary: Luteinizing hormone (LH) regulates ovulation and formation of the corpus luteum, while AMP-activated protein kinase (AMPK) exerts inhibitory effects on steroidogenesis in luteal cells by modulating the actions of PKA. AMPK regulates cholesterol availability for steroidogenesis by mediating phosphorylation of hormone-sensitive lipase (HSL), in contrast to the phosphorylation effects of LH/PKA on HSL.
Article
Immunology
Louise Blair, Michael J. Pattison, Probir Chakravarty, Stamatia Papoutsopoulou, Latifa Bakiri, Erwin F. Wagner, Stephen Smale, Steven C. Ley
Summary: TPL-2 kinase plays a crucial role in innate immunity and controls cellular immune response by regulating gene transcription. Activation of ERK1/2 and regulation of transcription factors, cytokines, etc., mediate the functions of TPL-2. The TCF-FOS pathway is involved in half of the transcriptional output of TPL-2, and the suppression of type I interferon signaling is critical for host resistance against bacterial infection.
JOURNAL OF IMMUNOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Charles W. Morgan, Ian L. Dale, Andrew P. Thomas, James Hunt, Jason W. Chin
Summary: In this study, bio-orthogonal ligand tethering (BOLT) was used to selectively target inhibitors to CRAF, showing that selective CRAF inhibition promotes paradoxical activation. This suggests that BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Coralie Dorard, Claire Madry, Olivier Buhard, Stefanie Toifl, Sebastian Didusch, Toky Ratovomanana, Quentin Letourneur, Helmut Dolznig, Mathew J. Garnett, Alex Duval, Manuela Baccarini
Summary: This study shows that RAF1 plays a crucial role in the proliferation of colorectal cancer and is independent of KRAS mutation status. RAF1 ablation decreases proliferation and STAT3 phosphorylation, indicating that RAF1 could be a therapeutic target for colorectal cancer.
Review
Cell Biology
Simon J. Cook, Pamela A. Lochhead
Summary: The RAS-regulated RAF-MEK1/2-ERK1/2 signaling pathway is frequently dysregulated in human cancer, particularly melanoma. Although three BRAFi have been approved for treating BRAF mutant melanoma and have shown significant impact, clinical responses are typically transient. Therefore, BRAFi are often used in combination with MEKi to provide more durable but still transient clinical responses. Recent studies have shown that activation of the ERK5 signaling pathway may result in resistance to BRAFi/MEKi and ERK1/2i.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Cell Biology
Chen Song, Yu Zhang, Yutong Li, Juntao Bie, Zhe Wang, Xin Yang, Haishuang Li, Liangyi Zhu, Tianzhuo Zhang, Qing Chang, Jianyuan Luo
Summary: During interphase, the phosphorylation cascade of TrkA-ERK1/2-ABL1-PHF5A plays a critical role in regulating centrosome separation, which involves the disruption of the centrosome linker. The pY36-PHF5A enhances the interaction between CEP250 and Nek2A, leading to premature centrosome separation. This cascade is hyper-regulated in medulloblastoma and inhibiting it can restrict tumor proliferation.
CELL DEATH & DISEASE
(2023)
Review
Biochemistry & Molecular Biology
Kumaresan Ramanathan, Minale Fekadie, Giri Padmanabhan, Henok Gulilat
Summary: Long noncoding RNAs (lncRNAs) play critical roles in kidney disease development and their dysregulation can lead to various disease processes. Understanding the function and potential application of lncRNAs in kidney disease may provide new diagnostic and therapeutic opportunities. This review provides an overview of lncRNA characteristics, function, and specific studies related to kidney disease treatment.
CELL BIOCHEMISTRY AND FUNCTION
(2024)