Article
Chemistry, Medicinal
Yin Sun, Yanli Xue, Pengkun Sun, Shuyi Mu, Hongbing Liu, Yu Sun, Lin Wang, Jingkai Wang, Tianxiao Wu, Wenbo Yin, Qiaohua Qin, Yixiang Sun, Nian Liu, Hanxun Wang, Huali Yang, Dongmei Zhao, Maosheng Cheng
Summary: A study discovered SP27 as the first selective PLK4 PROTAC degrader, which effectively degrades PLK4 and exhibits more potent inhibition of cell growth in TRIM37-amplified breast cancer. This finding is of great significance for the treatment of this cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
SeongShick Ryu, Jung-Eun Park, Young Jin Ham, Daniel C. Lim, Nicholas P. Kwiatkowski, Do-Hee Kim, Debabrata Bhunia, Nam Doo Kim, Michael B. Yaffe, Woolim Son, Namkyoung Kim, Tae-Ik Choi, Puspanjali Swain, Cheol-Hee Kim, Jin-Young Lee, Nathanael S. Gray, Kyung S. Lee, Taebo Sim
Summary: This study successfully designed and synthesized a series of macrocyclic peptidomimetics with high selectivity and inhibitory activities against Plk1's PBD. Compound 16e showed more potent inhibitory activity than the previous PMQSpTPL. The pi-π stacking interaction between 16a and Arg516 revealed a new design strategy, and PEGylation of 16h caused delocalization and mitotic failure of Plk1. Furthermore, the number of phospho-H3-positive cells in zebrafish embryos correlated with the amount of 16a. These findings suggest that macrocyclic peptidomimetics can serve as valuable templates for potent and novel Plk1-PBD inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Reinad R. Abu Rabah, Anusha Sebastian, Srinivasulu Vunnam, Shaista Sultan, Hamadeh Tarazi, Hanan S. Anbar, Mahmoud K. Shehata, Seyed-Omar Zaraei, Sara M. Elgendy, Salma A. Al Shamma, Hany A. Omar, Taleb H. Al-Tel, Mohammed El-Gamal
Summary: The study reports on a new series of pyrazole derivatives with potential anticancer activity. Compound 1f showed the most potent anticancer activity against various cancer cell lines, even more potent than sorafenib and SP600125. Compounds 1b, 1c, and 1h demonstrated strong anti-proliferative activity against hepatocellular carcinoma cell lines. The study also discovered two potent JNK3 inhibitors, compounds 1c and 1f, with good inhibitory effects in whole-cell assays.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Darshan Joshi, Rajesh Bahekar, Shubhangi Soman, Pradip Jadav, Dipam Patel, Amitgiri Goswami, Jignesh Pethani, Jeevan Kumar, Jitendra Patel, Rajesh Sundar, Poonamgiri Goswami, Krishnarup Goshdastidar, Hoshang Patel, Ankit Patel, Debdutta Bandyopadhyay, Abhijit Chattarjee, Manoranjan Sharma, Mukul Jain, Ranjit Desai
Summary: In this study, novel structural optimizations were conducted to discover effective Bruton's Tyrosine Kinase (BTK) inhibitors for the treatment of autoimmune disorders. Compound 14b was identified as a potent and selective BTK inhibitor with improved oral bioavailability. It displayed strong efficacy in in vitro and in vivo assays, making it a viable therapeutic option for autoimmune disorders.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Qiuyao Huang, Yan Zhong, Bingbing Li, Shumin Ouyang, Lin Deng, Jianshan Mo, Shuo Shi, Nan Lv, Ruibo Wu, Peiqing Liu, Wenhao Hu, Xiaolei Zhang, Yuanxiang Wang
Summary: In this study, we identified a number of highly potent and selective STAT3 inhibitors, with compound 39 showing promising inhibition of phosphorylation of STAT3 and suppression of downstream signaling pathways. Moreover, compound 39 demonstrated significant effects on cell growth, migration, and invasion of TNBC cells, as well as tumor growth inhibition in both cell line-derived and patient-derived xenograft models in mice.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Tony Eight Lin, Li-Chin Sung, Min-Wu Chao, Min Li, Jia-Huei Zheng, Tzu-Ying Sung, Jui-Hua Hsieh, Chia-Ron Yang, Hsueh-Yun Lee, Er-Chieh Cho, Kai-Cheng Hsu
Summary: This article reports the identification of a novel noncovalent BTK inhibitor that showed favorable inhibitory activity in solid tumor cell lines, suggesting its potential for targeting BTK malignant tumors.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Zhouling Xie, Xiaoxiao Yang, Yajun Duan, Jihong Han, Chenzhong Liao
Summary: Kinase inhibitors have been successful in treating various diseases beyond cancer, including autoimmune diseases and inflammatory diseases. Several non-oncologic small-molecule kinase inhibitors have been approved, with more in development for different applications.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Jian Yao, Yudong Yin, Hong Han, Shaoting Chen, Yuxiang Zheng, Benji Liang, Mengyue Wu, Kangqi Shu, Bikash Debnath, David B. Lombard, Quande Wang, Keguang Cheng, Nouri Neamati, Yanghan Liu
Summary: In this study, a novel SIRT5-selective inhibitor was identified and optimized, resulting in compound 47 with 100-fold improved potency. Compound 47 showed substantial selectivity for SIRT5 and acted as a substrate-competitive inhibitor. These findings provide possibilities for further research and development of therapeutic tools and drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Ava Safaroghli-Azar, Fatemeh Emadi, Jimma Lenjisa, Laychiluh Mekonnen, Shudong Wang
Summary: As the fifth pillar of cancer treatment, immunotherapy has revolutionized therapeutic strategies by focusing on the host's immune system. The discovery of immune-modulatory effects for kinase inhibitors has opened up new possibilities in this approach, as these small molecule inhibitors not only directly target essential proteins for tumor survival and proliferation, but also stimulate immune responses against malignant cells.
DRUG DISCOVERY TODAY
(2023)
Article
Oncology
Yuan He, Weiqiong Kan, Yunqi Li, Yun Hao, Anling Huang, Haijun Gu, Minna Wang, Qingqing Wang, Jinlian Chen, Zhenliang Sun, Mingyao Liu, Yihua Chen, Zhengfang Yi
Summary: The research found that MYOF promotes colorectal cancer cell invasion, and identified a novel inhibitor, YQ456, which can disrupt the interaction between MYOF and Rab proteins at low nanomolar levels and effectively inhibit the growth and invasion of colorectal cancer. This study suggests that targeting MYOF may be a novel and practical therapeutic approach for colorectal cancer.
CLINICAL AND TRANSLATIONAL MEDICINE
(2021)
Review
Biochemistry & Molecular Biology
Linwei Li, Songtao Liu, Bi Wang, Fei Liu, Shu Xu, Pirui Li, Yu Chen
Summary: Small molecule kinase inhibitors (SMKIs) play a crucial role in drug research and development, with numerous approved drugs and candidates in clinical trials. Computer-aided drug design (CADD) is essential in the discovery and optimization of SMKIs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Zhi Jian Zhong, Li Ping Cheng, Wan Pang, Xue Song Zheng, Shi Kai Fu
Summary: A dihydrofurocoumarin derivative was discovered as a lead NA inhibitor, with compound 5b showing the most potent activity against NA. The compound's potency may be attributed to the elongation of the dihydrofurocoumarin ring to the 150-cavity. These findings could be valuable in the discovery of more potent NA inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Mingyu Wang, Rongkun Lin, Jiacheng Li, Yuying Suo, Jing Gao, Liping Liu, Liyuan Zhou, Yicheng Ni, Ziqun Yang, Jie Zheng, Jin Lin, Hu Zhou, Cheng Luo, Hua Lin
Summary: In this study, a series of hydrophobic tagging-based degraders of the CDK8-cyclin C complex were designed, synthesized, and evaluated. The first dual degrader, LL-K8-22, was identified, which selectively degraded CDK8 and cyclin C. LL-K8-22 showed enhanced anti-proliferative effects and inhibited E2F-and MYC-driven carcinogenic transcriptional programs.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Chenghao Pan, Wenwen Nie, Jiao Wang, Jiamin Du, Zhichao Pan, Jian Gao, Yang Lu, Jinxin Che, Hong Zhu, Haibin Dai, Binhui Chen, Qiaojun He, Xiaowu Dong
Summary: This study developed a series of quinazoline derivatives based on the FGFR4 inhibitor BLU9931, with compound 35a showing improved stability in liver microsomes and induced apoptosis via FGFR4 signaling pathway blockage. Computational simulation provided insights into the binding mode of compound 35a to FGFR4 protein, explaining its high potency and metabolic stability.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Mukesh Gangar, Sandeep Goyal, Digambar Raykar, Princy Khurana, Ashwita M. Martis, Avijit Goswami, Ishani Ghoshal, Yadav Nagare, Santosh Raikar, Apurba Mukherjee, Rajath Cyriac, Jean-Francois Paquin, Aditya Kulkarni, Ketul Patel
Summary: ENPP1 is an attractive therapeutic target for cancer immunotherapy, acting as a critical phosphodiesterase that negatively regulates the STING pathway. Novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1 have shown promising in vitro potency and potent anti-tumor response in vivo, providing a good starting point for potentially effective cancer immunotherapy agents.
BIOORGANIC CHEMISTRY
(2022)