Article
Medicine, Research & Experimental
Pengxing He, Jing Jing, Linna Du, Xuyang Zhang, Yufei Ren, Han Yang, Bin Yu, Hongmin Liu
Summary: YS-363 is a novel EGFR inhibitor that demonstrates potent reversible inhibition and excellent activities against cell proliferation, migration, cell cycle and apoptosis. It is a promising selective inhibitor that can potentially be developed as a more effective anti-lung cancer agent targeting EGFR.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Chemistry, Medicinal
Kun-Hung Lee, Wan-Ching Yen, Wen-Hsing Lin, Pei-Chen Wang, You-Liang Lai, Yu-Chieh Su, Chun-Yu Chang, Cai-Syuan Wu, Yu-Chen Huang, Chen-Ming Yang, Ling-Hui Chou, Teng-Kuang Yeh, Chiung-Tong Chen, Chuan Shih, Hsing-Pang Hsieh
Summary: The study describes the discovery of orally active and selective CSF1R inhibitors, demonstrating their potent anti-tumor effects through in vivo experiments. By utilizing molecular docking and structural studies, the researchers were able to enhance the potency of the inhibitors and alter the tumor microenvironment to increase the M1/M2 ratio.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Zhonghua Li, Yong Yuan, Pan Wang, Zijuan Zhang, Huifen Ma, Yiran Sun, Xiaowei Zhang, Xiaofang Li, Yonghui Qiao, Feiyu Zhang, Yunfang Su, Junying Song, Zhishen Xie, Lixin Li, Liying Ma, Jinlian Ma, Zhenqiang Zhang
Summary: In this study, a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocyclic motif was reported, which showed nanomolar inhibitory potency against LSD1 and broad-spectrum antiproliferative activities against tumor cells. Compound 9j was identified as a selective and cellular active inhibitor, and showed remarkable efficacy in reducing tumor size and extending survival in a mouse model.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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
Biochemistry & Molecular Biology
Bin Wang, Youcai Liu, Lejing Zhang, Yajuan Wang, Zhaoxi Li, Xin Chen
Summary: In this paper, a series of novel compounds were designed as selective histone deacetylase 6 inhibitors. Compound 8f showed high inhibitory activity and selectivity, as well as good antiproliferative activity against multiple tumor cells.
Article
Oncology
Mariusz L. Hartman, Anna Gajos-Michniewicz, Julita A. Talaj, Aleksandra Mielczarek-Lewandowska, Malgorzata Czyz
Summary: Targeting therapies for BRAF(V600) and MEK1/2 rarely have lasting effects in melanoma patients. By studying BRAF(V600E) melanoma cell lines, it was found that encorafenib can modulate the balance of apoptosis-regulating proteins, predict induction of apoptosis, and demonstrate that MCL-1 is a druggable target to potentiate encorafenib activity.
Article
Chemistry, Medicinal
Janek Szychowski, Robert Papp, Evelyne Dietrich, Bingcan Liu, Frederic Vallee, Marie-Eve Leclaire, Jimmy Fourtounis, Giovanni Martino, Alexander L. Perryman, Victor Pau, Shou Yun Yin, Pavel Mader, Anne Roulston, Jean-Francois Truchon, C. Gary Marshall, Mohamed Diallo, Nicole M. Duffy, Rino Stocco, Claude Godbout, Alexanne Bonneau-Fortin, Rosie Kryczka, Vivek Bhaskaran, Daniel Mao, Stephen Orlicky, Patrick Beaulieu, Pascal Turcotte, Igor Kurinov, Frank Sicheri, Yael Mamane, Michel Gallant, W. Cameron Black
Summary: PKMYT1 acts as a regulator of CDK1 phosphorylation and has been identified as a potential therapeutic target for certain types of DNA damage response cancers. In this study, a weak inhibitor of PKMYT1 was identified and further optimized using structure-based drug design to improve its potency. The resulting potent and selective inhibitors, such as RP 6306, showed inhibitory effects on CCNE1-amplified tumor cell growth in preclinical xenograft models. RP 6306 is currently being evaluated in Phase 1 clinical trials for the treatment of various solid tumors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Shuqiang Chen, Kaijian Bi, Shanchao Wu, Yu Li, Yahui Huang, Chunquan Sheng, Guoqiang Dong
Summary: Novel water-soluble derivatives of 10-hydroxyevodiamine were synthesized, showing good antitumor activities, especially phosphate derivative 9. Further studies revealed that compound 9 induced apoptosis through multiple pathways, demonstrating promising antitumor efficacy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Zhe Shi, Jifang Weng, Haotao Niu, Hong Yang, Rongfeng Liu, Yan Weng, Qingqing Zhu, Yihong Zhang, Liangshan Tao, Zhenwu Wang, Seok Jae Huh, Yueheng Jiang, Hong Mei, Xing Dai, Ling Zhang, Yaolin Wang
Summary: D-1553 is a small molecule inhibitor targeting KRAS(G12C) that is currently in phase II clinical trials. Preclinical data demonstrated the antitumor activity of D-1553. It selectively and potently inhibits the mutated GDP-bound KRAS(G12C) protein and shows promising results in inhibiting tumor growth when used alone or in combination with other therapies.
Article
Chemistry, Medicinal
Andrew M. Griffin, Kristopher M. Kahlig, Robert John Hatch, Zoe A. Hughes, Mark L. Chapman, Brett Antonio, Brian E. Marron, Marion Wittmann, Gabriel Martinez-Botella
Summary: Variants in the KCNT1 gene lead to neurological disorders like epilepsy without effective treatments. Researchers have developed a novel oxadiazole compound, 31, which can reduce seizures in a mouse model of KCNT1-associated disease.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Weilin Chen, Xin Chen, Dongdong Li, Xianghan Wang, Guanlu Long, Zhengyu Jiang, Qidong You, Xiaoke Guo
Summary: The MLL1-WDR5 interaction is crucial for the formation of the MLL core complex and its H3K4 methyltransferase activity. Disrupting this interaction has been suggested as a potential therapeutic approach for leukemia. By developing a novel MLL1-WDR5 interaction blocker, the research team successfully identified the best inhibitor 24 with high binding affinity and improved drug-like properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Shun Zhang, Yan Zhao, Shuyuan Wang, Min Li, Yue Xu, Jianhua Ran, Xiaoqiang Geng, Jinzhao He, Jia Meng, Guangying Shao, Hong Zhou, Zemei Ge, Guangping Chen, Runtao Li, Baoxue Yang
Summary: A novel UT inhibitor was discovered in this study, showing excellent in vitro UT inhibitory activity and potential for treating hyponatremia accompanied with volume expansion without causing apparent toxicity or electrolyte imbalance.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Chemistry, Medicinal
Xiaobao Fang, Chunxiao Liu, Kun Zhang, Wanping Yang, Zewen Wu, Shige Shen, Yule Ma, Xun Lu, Yadong Chen, Tao Lu, Qinghua Hu, Yulei Jiang
Summary: This study discovered a series of novel, potent, and selective covalent BTK inhibitors through structure-based drug design, among which compound 36R exhibited high kinase selectivity, long target occupancy time, appropriate pharmacokinetic properties, and dose-dependent efficacy in a rat model of collagen-induced arthritis. Therefore, 36R is a novel BTK inhibitor requiring further development for the treatment of autoimmune diseases.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Hongchao Zheng, Jichen Zhao, Bing Li, Weihe Zhang, Michael A. Stashko, Katherine A. Minson, Madeline G. Huey, Yubai Zhou, Henry Shelton Earp, Dmitri Kireev, Douglas K. Graham, Deborah DeRyckere, Stephen Frye, Xiaodong Wang
Summary: Inhibition of MER receptor tyrosine kinase (MERTK) contributes to tumor cell killing and stimulation of the immune response. UNC5293 is a highly selective MERTK inhibitor with potent and selective inhibition in cell-based assays, excellent mouse PK properties, and activity in leukemia cells in a murine model.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Christiane Kofink, Nicole Trainor, Barbara Mair, Simon Woehrle, Melanie Wurm, Nikolai Mischerikow, Michael J. Roy, Gerd Bader, Peter Greb, Geraldine Garavel, Emelyne Diers, Ross McLennan, Claire Whitworth, Vesna Vetma, Klaus Rumpel, Maximilian Scharnweber, Julian E. Fuchs, Thomas Gerstberger, Yunhai Cui, Gabriela Gremel, Paolo Chetta, Stefan Hopf, Nicole Budano, Joerg Rinnenthal, Gerhard Gmaschitz, Moriz Mayer, Manfred Koegl, Alessio Ciulli, Harald Weinstabl, William Farnaby
Summary: Targeted protein degradation using bifunctional molecules provides a new therapeutic option for undruggable targets. In this study, the authors developed orally bioavailable VHL-recruiting degraders that selectively degrade SMARCA2, demonstrating the feasibility of broadening the E3 ligase and physicochemical space for achieving oral efficacy with bifunctional molecules.
NATURE COMMUNICATIONS
(2022)