Article
Oncology
John Hilton, Mihaela Cristea, Sophie Postel-Vinay, Capucine Baldini, Mark Voskoboynik, William Edenfield, Geoffrey Shapiro, Michael L. Cheng, Jacqueline Vuky, Bradley Corr, Sharmila Das, Abraham Apfel, Ke Xu, Martin Kozicki, Keziban Unsal-Kacmaz, Amy Hammell, Guan Wang, Palanikumar Ravindran, Georgia Kollia, Oriana Esposito, Shodeinde Coker, Jennifer R. Diamond
Summary: BMS-986158, an experimental anticancer therapy, can block BET protein function to regulate cancer-related genes and inhibit tumor growth. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158. Among the different dosing schedules tested, schedule A (5 days on, 2 days off) showed stable drug levels in the blood, preliminary anticancer effects, and a proportional PK profile.
Article
Biology
Mami Tsume-Kajioka, Chiharu Kimura-Yoshida, Kyoko Mochida, Yoko Ueda, Isao Matsuo
Summary: BET proteins are essential for the specification and maintenance of the epiblast lineage during mouse preimplantation development, with BRD4 playing a central role and BRD2 acting complementarily.
Article
Biochemistry & Molecular Biology
Ming Zou, Qin Ke, Qian Nie, Ruili Qi, Xingfei Zhu, Wei Liu, Xuebin Hu, Qian Sun, Jia-Ling Fu, Xiangcheng Tang, Yizhi Liu, David Wan-Cheng Li, Lili Gong
Summary: The dry form of age-related macular degeneration (AMD) is a major cause of vision loss. A study found that STING and cGAS expression is increased in the macular retinas of dry AMD patients. The activation of cGAS-STING was also observed in oxidative stress-induced mouse retina degeneration, and treatment with the BRD4 inhibitor JQ1 reduced this activation and alleviated inflammation and photoreceptor degeneration.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Biochemistry & Molecular Biology
Amjad Ali, Jasmin Shafarin, Hema Unnikannan, Nour Al-Jabi, Rola Abu Jabal, Khuloud Bajbouj, Jibran Sualeh Muhammad, Mawieh Hamad
Summary: Combined inhibition of BRD4-RAC1 signaling pathways shows promising antitumor effects in different molecular subtypes of breast cancer, suppressing cell growth, migration, and stem cell expansion while inducing autophagy and cellular senescence. Co-targeting RAC1-BRD4 presents a novel therapeutic approach by disrupting key axis and epigenetic regulation in breast tumorigenesis.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2021)
Article
Chemistry, Medicinal
Helen E. Aylott, Stephen J. Atkinson, Paul Bamborough, Anna Bassil, Chun-wa Chung, Laurie Gordon, Paola Grandi, James R. J. Gray, Lee A. Harrison, Thomas G. Hayhow, Cassie Messenger, Darren Mitchell, Alexander Phillipou, Alex Preston, Rab K. Prinjha, Francesco Rianjongdee, Inmaculada Rioja, Jonathan T. Seal, Ian D. Wall, Robert J. Watson, James M. Woolven, Emmanuel H. Demont
Summary: This study successfully reduced the genotoxicity risk of GSK046 by replacing the acetamide functionality with a heterocyclic ring, and identified potent, selective, and bioavailable compounds through a structure-based drug design approach.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Yoshiaki Tadokoro, Daisuke Takeda, Aki Murakami, Nanae Yatagai, Izumi Saito, Satomi Arimoto, Yasumasa Kakei, Masaya Akashi, Takumi Hasegawa
Summary: Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. Cancer-associated fibroblasts (CAFs) play a critical role in tumor progression. This study investigated the effect of transcutaneous carbon dioxide (CO2) application on CAFs marker expression and tumor growth in OSCC.
Article
Oncology
Aubrey L. Miller, Patrick L. Garcia, Samuel C. Fehling, Tracy L. Gamblin, Rebecca B. Vance, Leona N. Council, Dongquan Chen, Eddy S. Yang, Robert C. A. M. van Waardenburg, Karina J. Yoon
Summary: Gemcitabine combined with a BET bromodomain inhibitor showed superior efficacy in treating pancreatic cancer compared to Gemcitabine alone, potentially by inhibiting DNA repair protein expression and enhancing DNA damage, as well as impacting proteins involved in cholesterol biosynthesis and lipid metabolism. The combination therapy also selectively inhibited the LXR/RXR activation pathway, suggesting a mechanism for its observed in vivo efficacy.
Article
Chemistry, Medicinal
Junius Eugene Thomas, Mi Wang, Wei Jiang, Meilin Wang, Lu Wang, Bo Wen, Duxin Sun, Shaomeng Wang
Summary: The study describes the design, synthesis, and evaluation of potent PROTAC degraders (JET-209) targeting the transcriptional coactivators CBP and p300. JET-209 achieved high degradation potency for CBP and p300 in leukemia cell lines and demonstrated inhibition of tumor growth in xenograft models. JET-209 shows promise as a lead compound for developing CBP/p300 degraders for cancer treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Yi-Fan Zhang, Qing Li, Pei-Qi Huang, Tong Su, Shu-Heng Jiang, Li-Peng Hu, Xue-Li Zhang, Yue Sun, Hong Pan, Xiao-Mei Yang, Jun Li, Yan-Zhi Gai, Lei Zhu, Lin-Li Yao, Dong-Xue Li, Yong-Wei Sun, Zhi-Gang Zhang, De-Jun Liu, Yan-Li Zhang, Hui-Zhen Nie
Summary: This study identified FGD6 as a key regulator of macropinocytosis in pancreatic ductal adenocarcinoma (PDAC), promoting cell proliferation and tumor growth. FGD6 enhanced macropinocytosis by participating in the trans-Golgi network and promoting the membrane localization of growth factor receptors, particularly the TGF-beta receptor. Clinical data analysis showed that high expression of FGD6 was correlated with poor prognosis in PDAC patients.
Article
Chemistry, Medicinal
Francesco Rianjongdee, Stephen J. Atkinson, Chun-Wa Chung, Paola Grandi, James R. J. Gray, Laura J. Kaushansky, Patricia Medeiros, Cassie Messenger, Alex Phillipou, Alex Preston, Rab K. Prinjha, Inmaculada Rioja, Alexander L. Satz, Simon Taylor, Ian D. Wall, Robert J. Watson, Gang Yao, Emmanuel H. Demont
Summary: This study presents the discovery of a novel BET BD2-selective compound with unique structural features, exceptional selectivity, and good physicochemical properties, which can potentially advance the field of epigenetics research.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Gautam Borthakur, Olatoyosi Odenike, Ibrahim Aldoss, David A. Rizzieri, Thomas Prebet, Chris Chen, Relja Popovic, Dimple A. Modi, Rujuta H. Joshi, Johannes E. Wolff, Brian A. Jonas
Summary: The study investigated the safety and efficacy of the pan-BET inhibitor mivebresib as monotherapy and in combination with venetoclax in patients with relapsed/refractory AML. Adverse effects of the drug were dose-dependent, and some patients showed improvement in their leukemia. Further studies are needed to determine the potential of mivebresib in treating acute myeloid leukemia.
Article
Chemistry, Medicinal
Haibo Xie, Megan S. Bacabac, Min Ma, Eui-Jun Kim, Yidan Wang, Wenxin Wu, Lingjun Li, Wei Xu, Weiping Tang
Summary: CARM1 is frequently amplified or overexpressed in various cancer types and is associated with poor prognosis. In this study, researchers developed a proteolysis targeting chimera (PROTAC) for CARM1, which effectively degraded CARM1 and inhibited cancer cell migration. These findings suggest that CARM1 PROTACs have the potential to be developed as therapeutic agents for CARM1-driven cancers.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Cho-Hao Lin, Jimmy Chun-Tien Kuo, Ding Li, Aaron B. Koenig, Alexander Pan, Pearlly Yan, Xue-Feng Bai, Robert J. Lee, Kalpana Ghoshal
Summary: This study identified novel targets of BRD4 in the HCCLM3 cell genome and demonstrated the anti-HCC efficacy of AZD5153, which was potentiated in combination with an NAMPT inhibitor.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Pharmacology & Pharmacy
Yanli Sun, Jie Han, Zhanzhao Wang, Xuening Li, Yanhua Sun, Zhenbo Hu
Summary: The upregulated expression of BET proteins is closely related to hematological malignancies and solid tumors. Ten BET inhibitors currently in clinical trials showed exposure-dependent thrombocytopenia, and further efforts are needed to explore optimal dosing schemes for maximizing their efficacy.META_DESCRIPTION
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Tao Yang, Shuren Zhang, Hao Yuan, Ying Wang, Linxiang Cai, Hanhua Chen, Xiaoyu Wang, Dongfan Song, Xiaohui Wang, Zijian Guo, Xiaoyong Wang
Summary: Triggering receptor expressed on myeloid cells-2 (TREM2) is a marker of tumor-infiltrating macrophages with immunosuppressive activity in the tumor microenvironment. The platinum(IV) complex OPA derived from oxaliplatin and artesunate has direct cytotoxicity against human colon cancer cells and inhibits TREM2 on macrophages in vitro and vivo. Furthermore, OPA reduces immunosuppressive macrophages and promotes the expansion and infiltration of immune-stimulating cells.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)