Review
Neurosciences
Henry Querfurth, Han-Kyu Lee
Summary: mTOR is involved in regulating energy metabolism, neuronal growth, insulin signaling, and autophagy, playing both beneficial and pathogenic roles in neurodegenerative diseases. Balanced actions of mTOR complexes may have implications for Alzheimer's disease, Parkinson's disease, Huntington's disease, Frontotemporal dementia, and Amyotrophic Lateral Sclerosis. Beyond rapamycin, rapalogs with improved tolerability and delivery modes hold promise in treating age-related conditions.
MOLECULAR NEURODEGENERATION
(2021)
Article
Multidisciplinary Sciences
Douglas R. Wassarman, Kondalarao Bankapalli, Leo J. Pallanck, Kevan M. Shokat
Summary: Mammalian target of rapamycin (mTOR) is a crucial factor in cell growth and metabolism, and its signaling in different tissues affects whole-organism processes. Researchers have developed selecTOR, a chemical-genetic system that restricts the activity of rapamycin analog in specific cell populations, achieving selective mTOR inhibition.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Medicine, Research & Experimental
Mohamed El-Tanani, Hamdi Nsairat, Alaa A. Aljabali, Angel Serrano-Aroca, Vijay Mishra, Yachana Mishra, Gowhar A. Naikoo, Walhan Alshaer, Murtaza M. Tambuwala
Summary: The mammalian target of rapamycin (mTOR), a signalling system, is necessary for various cell proliferation activities. It recognizes PI3KAKT stress signals as a serine-threonine kinase. The abnormal regulation of mTOR pathway has been proven to be crucial in cancer growth and advancement. This review primarily discusses the normal functions of mTOR as well as its abnormal roles in cancer development.
Article
Biochemistry & Molecular Biology
Alaa Abou Daher, Sahar Alkhansa, William S. Azar, Rim Rafeh, Hilda E. Ghadieh, Assaad A. Eid
Summary: Understanding the mechanisms behind diabetic nephropathy (DN) is crucial for developing effective treatments. The mTOR pathway has been identified as a key player in diabetes-induced kidney injury, through its involvement in insulin resistance, oxidative stress, and autophagy regulation.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Article
Ophthalmology
Nozomi Igarashi, Megumi Honjo, Makoto Aihara
Summary: Glaucoma, the second leading cause of blindness worldwide, is often treated with trabeculectomy, but this surgery can lead to excessive scarring and tissue fibrosis. Studies have shown that mTOR inhibitors may offer a new treatment modality for reducing fibrotic response in human conjunctival fibroblasts and improving bleb scarring after filtration surgery.
EXPERIMENTAL EYE RESEARCH
(2021)
Article
Immunology
Preeti Vyas, Rajkumar Tulsawani, Divya Vohora
Summary: Recent findings show that neuroinflammation is closely related to seizures, and the PI3K/Akt/mTOR pathway is speculated to be a potential target for treating neuroinflammation-mediated seizures and neurodegeneration. In a study on mice, PI3K inhibitors buparlisib and dactolisib were found to be effective in prolonging seizure latency and reducing neuronal loss, while rapamycin showed some resistance. The study suggests that targeting the PI3K pathway may offer new approaches for seizure therapies.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Pharmacology & Pharmacy
Timothy Crook, Darshana Patil, Andrew Gaya, Nicholas Plowman, Sewanti Limaye, Anantbhushan Ranade, Amit Bhatt, Raymond Page, Dadasaheb Akolkar
Summary: The study demonstrated that patient-specific combination regimens with mTOR inhibition and other anti-neoplastic agents, selected based on multi-analyte molecular and functional profiling of the tumor, can result in meaningful outcomes in advanced or refractory solid organ cancers.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Surgery
Sunbin Ling, Qifan Zhan, Guangjiang Jiang, Qiaonan Shan, Lu Yin, Rui Wang, Qingyang Que, Xuyong Wei, Shengjun Xu, Jiongjie Yu, Wei Zhou, Lincheng Zhang, Jiaqi Bao, Qianwei Ye, Renyi Su, Rongli Wei, Jimin Liu, Kangchen Chen, Jingrui Wang, Haiyang Xie, Shusen Zheng, Xin He, Jiajia Xiang, Xiao Xu
Summary: This study discovered that E2F7 gene induces and promotes resistance to mTOR inhibitor sirolimus in HCC under hypoxic conditions. This is achieved by suppressing mTOR complex 1 and activating hypoxia-inducible factor-1 alpha and its downstream genes. Low expression of E2F7 can serve as an effective biomarker for predicting the response to anti-mTOR-based therapies after LT in HCC patients. Targeting E2F7 synergistically inhibits HCC growth with sirolimus.
AMERICAN JOURNAL OF TRANSPLANTATION
(2022)
Article
Biotechnology & Applied Microbiology
Andrea Perez-Iturralde, Beatriz Carte, Rafael Aldabe
Summary: The study found that mTOR inhibitors have complex effects on AAV hepatic transduction efficiency, with rapamycin enhancing AAV transduction while RapaLink-1 and MLN0128 do not. This indicates that mTOR inhibition is not a straightforward strategy for improving AAV transduction, and more research is needed to elucidate the mechanisms involved in their effects.
HUMAN GENE THERAPY
(2021)
Article
Oncology
Fan Lin, Yunqi Liu, Lili Tang, Xiaohui Xu, Xueli Zhang, Yifan Song, Bicheng Chen, Yeping Ren, Xiangdong Yang
Summary: The study demonstrated that rapamycin protects against aristolochic acid-induced nephropathy by activating the mTOR-autophagy axis. This finding provides evidence for rapamycin as a promising pharmacological target for the treatment of aristolochic acid nephropathy.
MOLECULAR MEDICINE REPORTS
(2021)
Review
Biochemistry & Molecular Biology
Vivek Panwar, Aishwarya Singh, Manini Bhatt, Rajiv K. Tonk, Shavkatjon Azizov, Agha Saquib Raza, Shinjinee Sengupta, Deepak Kumar, Manoj Garg
Summary: mTOR is a protein kinase that regulates cellular metabolism, immune responses, autophagy, and other cellular processes. Its signaling cascade plays important roles in translation, biogenesis of biomolecules, immune responses, and autophagy. Aberrant activation of the mTOR pathway is associated with aging, neurological disorders, and human malignancies.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2023)
Review
Chemistry, Medicinal
Patrik Oleksak, Eugenie Nepovimova, Zofia Chrienova, Kamil Musilek, Jiri Patocka, Kamil Kuca
Summary: Mechanistic target of rapamycin (mTOR) is a protein kinase that regulates cell functions. Dysregulation of mTOR activity is associated with various pathological conditions. Inhibition of overactivated mTOR is a rational approach for treating human diseases. Rapamycin is a natural inhibitor of mTOR with antitumor and immunosuppressive activity. Different generations of mTOR inhibitors have been developed, including rapalogs, mTOR kinase inhibitors, and dual PI3K/mTOR inhibitors. Novel inhibitors are still being developed to better understand the role of mTOR in signaling pathways and human diseases.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Immunology
Jun Zeng, Qiang Zhong, Xiaobing Feng, Linde Li, Shijian Feng, Yu Fan, Turun Song, Zhongli Huang, Xianding Wang, Tao Lin
Summary: Conversion from CNIs to mTORi therapy in kidney transplant recipients can improve renal function and reduce the incidence of malignancy, but is associated with a higher risk of adverse events such as acute rejection, infection, proteinuria, leukopenia, acne, and mouth ulcer, leading to increased drug discontinuation rates. The conversion strategy may be suitable for selected patients.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Chemistry, Medicinal
Zhaoping Pan, Yi Chen, Haiying Pang, Xiaoyun Wang, Yuehua Zhang, Xin Xie, Gu He
Summary: A novel class of thieno [2,3-d] pyrimidine derivatives containing resorcinol and morpholine fragments as Hsp90/mTOR dual inhibitors were designed, synthesized, and evaluated. The most potent compound 17o showed remarkable inhibitory activities on Hsp90, mTOR, and SW780 cancer cell, both in vitro and in vivo. Mechanism studies revealed that 17o suppressed cell proliferation through the over-activation of the PI3K/AKT/mTOR pathway regulated by mTOR inhibition and apoptosis regulated by the mitochondrial pathway.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Jianya Huan, Petros Grivas, Jasmine Birch, Donna E. Hansel
Summary: The mammalian target of rapamycin (mTOR) pathway plays a crucial role in cell growth and metabolism. Dysregulation of this pathway can promote cancer growth and progression. Approximately 70% of bladder cancer (UC) cases show abnormal mTOR activity, indicating its key role in this cancer. This review highlights the importance of mTOR signaling in UC and its potential implications for future therapy. Despite extensive research on molecular alterations of the mTOR pathway in bladder cancer, there has been limited success in mTOR-targeted therapy. Further understanding of the signaling convergence onto mTOR complexes in bladder cancer may provide valuable insights for the treatment of this aggressive disease.
Article
Hematology
Emily Rychak, Derek Mendy, Tao Shi, Yuhong Ning, Jim Leisten, Ling Lu, Karen Miller, Rama K. Narla, Robert Z. Orlowski, Heather K. Raymon, Chad C. Bjorklund, Anjan Thakurta, Anita K. Gandhi, Brian E. Cathers, Rajesh Chopra, Thomas O. Daniel, Antonia Lopez-Girona
BRITISH JOURNAL OF HAEMATOLOGY
(2016)
Article
Multidisciplinary Sciences
Mary E. Matyskiela, Gang Lu, Takumi Ito, Barbra Pagarigan, Chin-Chun Lu, Karen Miller, Wei Fang, Nai-Yu Wang, Derek Nguyen, Jack Houston, Gilles Carmel, Tam Tran, Mariko Riley, Lyn'Al Nosaka, Gabriel C. Lander, Svetlana Gaidarova, Shuichan Xu, Alexander L. Ruchelman, Hiroshi Handa, James Carmichael, Thomas O. Daniel, Brian E. Cathers, Antonia Lopez-Girona, Philip P. Chamberlain
Article
Chemistry, Medicinal
Mary E. Matyskiela, Weihong Zhang, Hon-Wah Man, George Muller, Godrej Khambatta, Frans Baculi, Matthew Hickman, Laurie LeBrun, Barbra Pagarigan, Gilles Carmel, Chin-Chun Lu, Gang Lu, Mariko Riley, Yoshitaka Satoh, Peter Schafer, Thomas O. Daniel, James Carmichael, Brian E. Cathers, Philip P. Chamberlain
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Multidisciplinary Sciences
Thang Van Nguyen, Jing Li, Chin-Chun (Jean) Lu, Jennifer L. Mamrosh, Gang Lu, Brian E. Cathers, Raymond J. Deshaies
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2017)
Article
Oncology
Toshiya Tsuji, Lisa M. Sapinoso, Tam Tran, Bonny Gaffney, Lilly Wong, Sabita Sankar, Heather K. Raymon, Deborah S. Mortensen, Shuichan Xu
Article
Chemistry, Medicinal
Sreedhar R. Tummalapalli, Rohit Bhat, Agnieszka Chojnowski, Monika Prorok, Tamara Kreissir, Ronald Goldberg, Stacie Canan, Natalie Hawryluk, Deborah Mortensen, Vikram Khetan, Jerome Zeldis, John J. Siekierka, David P. Rotella
ACS MEDICINAL CHEMISTRY LETTERS
(2018)
Article
Biology
Gang Lu, Stephanie Weng, Mary Matyskiela, Xinde Zheng, Wei Fang, Scott Wood, Christine Surka, Reina Mizukoshi, Chin-Chun Lu, Derek Mendy, In Sock Jang, Kai Wang, Mathieu Marella, Suzana Couto, Brian Cathers, James Carmichael, Philip Chamberlain, Mark Rolfe
Article
Chemistry, Medicinal
Joshua D. Hansen, Matthew Correa, Mark A. Nagy, Matt Alexander, Veronique Plantevin, Virginia Grant, Brandon Whitefield, Dehua Huang, Timothy Kercher, Roy Harris, Rama Krishna Narla, Jim Leisten, Yang Tang, Mehran Moghaddam, Katalin Ebinger, Joseph Piccotti, Courtney G. Havens, Brian Cathers, James Carmichael, Thomas Daniel, Rupert Vessey, Lawrence G. Hamann, Katerina Leftheris, Derek Mendy, Frans Baculi, Laurie A. LeBrun, Gody Khambatta, Antonia Lopez-Girona
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Joshua D. Hansen, Matthew Correa, Matt Alexander, Mark Nagy, Dehua Huang, John Sapienza, Gang Lu, Laurie A. LeBrun, Brian E. Cathers, Weihong Zhang, Yang Tang, Massimo Ammirante, Rama K. Narla, Joseph R. Piccotti, Michael Pourdehnad, Antonia Lopez-Girona
Summary: Acute myeloid leukemia poses a significant clinical challenge with poor survival and high relapse rates. CC-90009, a novel protein degrader targeting GSPT1 for proteasomal degradation, represents a promising therapeutic approach currently in phase 1 clinical development.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Microbiology
Rokeya Tasneen, Deborah S. Mortensen, Paul J. Converse, Michael E. Urbanowski, Anna Upton, Nader Fotouhi, Eric Nuermberger, Natalie Hawryluk
Summary: Host-directed therapy (HDT) is being explored as a potential approach to enhance immune defenses against Mycobacterium tuberculosis. Inhibiting mTOR signaling may be an effective strategy within this framework.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Cardiac & Cardiovascular Systems
Kobina Dufu, Alexander T. Williams, Cynthia R. Muller, Cynthia M. Walser, Alfredo Lucas, Allyn M. Eaker, Carsten Alt, Brian E. Cathers, Donna Oksenberg, Pedro Cabrales
Summary: The study suggests that increasing hemoglobin affinity for oxygen can improve the survival rate and brain tissue oxygenation of SCD mice under hypoxic conditions.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2021)
Article
Chemistry, Medicinal
Patrick Papa, Brandon Whitefield, Deborah S. Mortensen, Dan Cashion, Dehua Huang, Eduardo Torres, Jason Parnes, John Sapienza, Joshua Hansen, Matthew Correa, Mercedes Delgado, Roy Harris, Sayee Hegde, Stephen Norris, Sogole Bahmanyar, Veronique Plantevin-Krenitsky, Zheng Liu, Katerina Leftheris, Ashutosh Kulkarni, Brydon Bennett, Eun Mi Hur, Garth Ringheim, Godrej Khambatta, Henry Chan, Jeffrey Muir, Kate Blease, Kelven Burnett, Laurie LeBrun, Lisa Morrison, Maria Celeridad, Roli Khattri, Brian E. Cathers
Summary: The study focused on the synthesis and structure-activity relationship of a novel series of PKC-theta inhibitors, aiming to identify suitable replacements for the basic C4 amine and to explore SAR for potent analogs with metabolic stability and permeability for in vivo testing. The selected compound CC-90005 showed general kinase selectivity, inhibition of T cell activation, a favorable safety profile, and efficacy in models of acute and chronic T cell activation, leading to its selection for clinical development.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Mark A. Nagy, Robert Hilgraf, Deborah S. Mortensen, Jan Elsner, Stephen Norris, Jayashree Tikhe, Won Yoon, David Paisner, Mercedes Delgado, Paul Erdman, Jason Haelewyn, Godrej Khambatta, Li Xu, William J. Romanow, Kevin Condroski, Sogole Bahmanyar, Meg McCarrick, Brent Benish, Kate Blease, Laurie LeBrun, Mehran F. Moghaddam, Julius Apuy, Stacie S. Canan, Brydon L. Bennett, Yoshitaka Satoh
Summary: A novel series of JNK inhibitors with increased JNK1 bias have been identified through synthesis and SAR studies, showing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Physiochemical optimization in this series led to compounds with excellent systemic exposure post oral dosing, leading to the selection of a clinical development candidate, CC-90001, currently in Phase II trials for patients with idiopathic pulmonary fibrosis.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Deborah S. Mortensen, Sayee G. Hegde, Sophie M. Perrin-Ninkovic, Sogole Bahmanyar, Meg McCarrick, Roy Harris, Robert Hilgraf, Branden G. S. Lee, Jeff McKie, Lisa Nadolny, John Sapienza, Alice Collette, Sarah Cox, James C. Gamez, Jennifer L. Hensel, Xuequn Helen Hua, Jim Leisten, Heather K. Raymon, Tam Tran, Rama Krishna Narla
Summary: We have discovered and optimized a novel series of AKT kinase inhibitors, guided by the structure of the target protein. Docking studies led to the development of a potent series of N-substituted-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amines. These compounds inhibit the AKT pathway in cancer cells by suppressing the phosphorylation of pathway proteins pGSK and pFKHR. In vivo studies using compound 12 showed inhibition of phosphorylation of the direct substrate GSK and pathway biomarker S6 in tumor-bearing mice.
MEDICINAL CHEMISTRY RESEARCH
(2023)
