Article
Chemistry, Medicinal
Huachao Bin, Pei Chen, Ming Wu, Falu Wang, Guifeng Lin, Shulei Pan, Jingming Liu, Bo Mu, Jinshan Nan, Qiao Huang, Linli Li, Shengyong Yang
Summary: This study reports the discovery of a potent and highly selective ATR inhibitor, SKLB-197, which demonstrated strong activity against ATR and weak or no activity against other protein kinases. SKLB-197 showed significant antitumor activity against ATM-deficient tumors both in vitro and in vivo, and it exhibited favorable pharmacokinetic properties. These findings suggest that SKLB-197 could be a promising lead compound for drug discovery targeting ATR.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Danli Zhou, Yingying Zuo, Zhengying Pan
Summary: This study reports the development of cereblon-recruiting ITK proteolysis targeting chimeras based on a structure-based design strategy, which holds great therapeutic potential for human autoimmune diseases and T-cell malignant lymphomas. Two representative compounds, 23 and 28, demonstrated potent ITK degradation and IL-2 inhibition activities in Jurkat cells. Global proteomic profiling assays confirmed the high selectivity of compounds 23 and 28 as ITK degraders. Compound 28 exhibited efficient, rapid, and prolonged ITK degradation in mice, along with significant suppression of IL-2 secretion. It is the first effective and highly selective ITK degrader, serving as a valuable tool compound for further investigation of ITK degradation in human diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Zhanhui Li, Yongjin Hao, Chengkui Yang, Qing Yang, Shuwei Wu, Haikuo Ma, Sheng Tian, Haohao Lu, Jingrui Wang, Tao Yang, Sudan He, Xiaohu Zhang
Summary: This study reports a series of potent RIPK1 inhibitors, with compound 70 being highly active and stable in blocking necroptosis in inflammatory signaling and cell death. Compound 70 exhibits excellent properties and activity in both in vitro and in vivo experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Medicine, Research & Experimental
Frank P. Vendetti, Pinakin Pandya, David A. Clump, Sandra Schamus-Haynes, Meysam Tavakoli, Maria diMayorca, Naveed M. Islam, Jina Chang, Greg M. Delgoffe, Jan H. Beumer, Christopher J. Bakkenist
Summary: Inhibitors of the ATR kinase can enhance the killing of tumor cells by DNA replication fork-targeting chemotherapies but also affect rapidly proliferating immune cells. Combining ATR inhibitor and radiotherapy can stimulate CD8+ T cell-dependent antitumor responses. The optimal schedule of ATR inhibitor and radiotherapy is determined by the duration of ATR inhibitor treatment, which affects the expansion of tumor antigen-specific CD8+ T cells.
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
Oncology
Shinnosuke Harata, Takuya Suzuki, Hiroki Takahashi, Takahisa Hirokawa, Akira Kato, Kaori Watanabe, Takeshi Yanagita, Hajime Ushigome, Kazuyoshi Shiga, Ryo Ogawa, Akira Mitsui, Masahiro Kimura, Yoichi Matsuo, Shuji Takiguchi
Summary: Combination therapy with ATR inhibitor AZD6738 and FTD enhanced the inhibition of tumor proliferation in vitro and in vivo, suggesting a potential treatment strategy for colorectal cancer.
Article
Pharmacology & Pharmacy
Longxiang Huang, Zhenni Wei, Xiaohui Wang, Chunlin Lan, Yihua Zhu, Qin Ye
Summary: This study demonstrates that AZD6738 can decrease intraocular pressure and inhibit fibrotic response in the eye, offering a potential therapeutic option for glaucoma treatment.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yongjin Hao, Chengkui Yang, Chang Shu, Zhanhui Li, Kaijiang Xia, Shuwei Wu, Haikuo Ma, Sheng Tian, Yuting Ji, Jingjing Li, Sudan He, Xiaohu Zhang
Summary: This study identified compound 36 as an inhibitor of necroptosis and optimized its scaffold to obtain a series of potent compounds. Among them, compound 56 showed excellent pharmacological properties, effectively binding and inhibiting RIPK1, and had the potential for treating inflammation-related diseases.
BIOORGANIC CHEMISTRY
(2022)
Article
Oncology
Monika Caban, Bettina Koblmueller, Diana Groza, Hemma H. Schueffl, Alessio Terenzi, Alexander Tolios, Thomas Mohr, Marlene Mathuber, Kushtrim Kryeziu, Carola Jaunecker, Christine Pirker, Bernhard K. Keppler, Walter Berger, Christian R. Kowol, Petra Heffeter
Summary: Through chemical modifications, KP2187 has similar activity and action as other clinically used EGFR inhibitors, without interfering with EGFR binding. In vitro and in vivo experiments have shown that KP2187 can significantly inhibit tumor cell proliferation and activate the EGFR signaling pathway. Moreover, KP2187 has a high synergistic effect with VEGFR inhibitors, indicating its potential as a hypoxia-activated prodrug.
Article
Biotechnology & Applied Microbiology
Hannah I. Ghasemi, Julien Bacal, Amanda C. Yoon, Katherine U. Tavasoli, Carmen Cruz, Jonathan T. Vu, Brooke M. Gardner, Chris D. Richardson
Summary: The efficiency of gene editing via homology-directed repair (HDR) can be enhanced by covalently modifying the template DNA to form interstrand crosslinks. These crosslinked templates (xHDRTs) significantly increase Cas9-mediated editing efficiencies in various cell types. The increased editing from xHDRTs is dependent on events occurring on the template molecule and requires the ATR kinase and components of the Fanconi anemia pathway.
NATURE BIOTECHNOLOGY
(2023)
Article
Pharmacology & Pharmacy
Longxiang Huang, Qin Ye, Chunlin Lan, Xiaohui Wang, Yihua Zhu
Summary: In this study, it was found that AZD6738 can inhibit the fibrotic response of conjunctival fibroblasts, potentially serving as a therapeutic option for anti-subconjunctival scarring after trabeculectomy.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Xufen Yu, Jia Xu, Yudao Shen, Kaitlyn M. Cahuzac, Kwang-Su Park, Brandon Dale, Jing Liu, Ramon E. Parsons, Jian Jin
Summary: In this study, we reported a potent AKT degrader MS21 and its structure-activity relationship (SAR) studies. Additionally, we discovered another VHL-recruiting AKT degrader MS143 with similar efficacy as MS21, as well as a novel CRBN-recruiting PROTAC MS5033. These compounds effectively degraded AKT by hijacking the ubiquitin-proteasome system and showed significant inhibition of cell growth in multiple cancer cell lines. Furthermore, they exhibited good plasma exposure levels in mice and were suitable for in vivo studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Xiaofei Liang, Chun Wang, Beilei Wang, Juan Liu, Shuang Qi, Aoli Wang, Qingwang Liu, Maoqing Deng, Li Wang, Jing Liu, Qingsong Liu
Summary: CSF1R kinase is crucial in tumor-associated macrophage repolarization, and the selective inhibitor 18h shows potent inhibition against CSF1R with significant selectivity, leading to suppression of tumor growth.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Atsunori Kaneshige, Longchuan Bai, Mi Wang, Donna McEachern, Jennifer L. Meagher, Renqi Xu, Paul D. Kirchhoff, Bo Wen, Duxin Sun, Jeanne A. Stuckey, Shaomeng Wang
Summary: We discovered a potent and selective STAT5 degrader with strong antitumor activity in vivo. Using PROTAC technology, we transformed small-molecule ligands into selective STAT5 degraders, with AK-2292 as the best compound. AK-2292 effectively induced degradation of STAT5 proteins in AML cell lines and showed strong antitumor activity in mice.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Nanang Rudianto Ariefta, Baldorj Pagmadulam, Coh-ichi Nihei, Yoshifumi Nishikawa
Summary: This study evaluated the growth-inhibitory effects of the antimalarial agent sparsomycin against drug-resistant malaria parasites. The results showed that sparsomycin had inhibitory effects on both sensitive and resistant strains of the parasites. This study suggests that sparsomycin has potential as an alternative treatment for malaria.
