Article
Chemistry, Medicinal
Wei Yan, Lingtian Zhang, Fengping Lv, Marialuisa Moccia, Francesca Carlomagno, Christophe Landry, Massimo Santoro, Fabien Gosselet, Brendan Frett, Hong-yu Li
Summary: This paper describes the discovery of a novel type-II pan-TRK inhibitor with significant anti-cancer activity, which could serve as a potential therapeutic drug for treating TRK-driven cancers.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Mu-Chun Li, Wen-Hsing Lin, Pei-Chen Wang, Yu-Chieh Su, Pei-Yi Chen, Chu-Min Fan, Ching-Ping Chen, Chen-Lung Huang, Chun-Hsien Chiu, Ling Chang, Chiung-Tong Chen, Teng-Kuang Yeh, Hsing-Pang Hsieh
Summary: The rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling, leading to various solid tumors in adults and children. Compound 39, designed and synthesized based on the architecture of the multi-targeted clinical candidate BPR1K871, showed high selectivity for TRKA, potent cellular activity, good oral bioavailability, and in vivo efficacy in a xenograft model, making it a promising next-generation, selective, orally-administered type II TRK inhibitor.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Zuqin Wang, Jie Wang, Yongjin Wang, Shuang Xiang, Xiaojuan Song, Zhengchao Tu, Yang Zhou, Zhi-Min Zhang, Zhang Zhang, Ke Ding, Xiaoyun Lu
Summary: In this study, a novel TRK inhibitor 7b was reported. It is a highly selective macrocycle-based potent type II inhibitor that exhibits high inhibitory activity against TRK fusion proteins and wild type. Additionally, 7b showed potent antiproliferative activity against various mutants and displayed extraordinary selectivity for phosphorylation.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Zongliang Liu, Pengfei Yu, Lin Dong, Wenyan Wang, Sijin Duan, Bingsi Wang, Xiaoyan Gong, Liang Ye, Hongbo Wang, Jingwei Tian
Summary: The study reports the identification and optimization of macrocyclic compounds as potent pan-Trk inhibitors, showing good activity against wild and mutant TrkA/TrkC in in vitro and in vivo studies. Compound 10, identified through optimization, demonstrated good activity against wild and mutant TrkA/TrkC in both chemistry and pharmacokinetics.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Medicine, General & Internal
Shuja Sheikh, Usman Alvi, Betty Soliven, Kourosh Rezania
Summary: This review summarizes the drugs that can cause de novo MG, MG exacerbation, or MG-like symptoms in patients without myasthenia gravis, providing a better understanding of the mechanisms behind these adverse effects.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Chemistry, Multidisciplinary
Meng-di Dai, Yue-liang Wang, Jun Fan, Yang Dai, Yin-chun Ji, Yi-ming Sun, Xia Peng, Lan-lan Li, Yu-ming Wang, Wen-hu Duan, Jian Ding, Jing Ai
Summary: DW14383 is a promising selective irreversible pan-FGFR inhibitor with pan-tumor spectrum potential in FGFR1-4 aberrant cancers, which has the potential to overcome compensatory activation among FGFR1-4.
ACTA PHARMACOLOGICA SINICA
(2021)
Article
Multidisciplinary Sciences
Simon Strohmeier, Iva Brcic, Helmut Popper, Bernadette Liegl-Atzwanger, Joerg Lindenmann, Luka Brcic
Summary: The study found a low occurrence of NTRK fusions in lung carcinomas and low expression of pan-TRK across different histologic types. Molecular methods are essential for confirming immunohistochemistry results.
SCIENTIFIC REPORTS
(2021)
Review
Pharmacology & Pharmacy
Tingting Jiang, Guan Wang, Yao Liu, Lu Feng, Meng Wang, Jie Liu, Yi Chen, Liang Ouyang
Summary: TRKA, TRKB, and TRKC are important members of the cell surface receptor tyrosine kinase family, regulating cell proliferation, differentiation, and apoptosis. NTRK gene fusions act as oncogenic drivers for a variety of tumors, making TRK inhibitors promising targets for anti-tumor therapy.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Multidisciplinary Sciences
Francisco Martinez-Jimenez, Ali Movasati, Sascha Remy Brunner, Luan Nguyen, Peter Priestley, Edwin Cuppen, Arne Van Hoeck
Summary: This study characterizes the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors. Metastatic tumors have lower heterogeneity and a conserved karyotype, with only a modest increase in mutations. Most cancer types show either moderate or consistent genomic differences between early-stage and late-stage disease, except for breast, prostate, thyroid, kidney renal clear cell carcinomas, and pancreatic neuroendocrine tumors, which exhibit extensive genetic landscape transformation in advanced stages.
Article
Chemistry, Medicinal
Yanle Zhi, Hongmei Li, Pei Yang, Qiaomei Jin, Chao Yao, Baoquan Li, Jun Ling, Hao Guo, Tonghui Li, Jianlin Jin, Yue Wang, Yadong Chen, Tao Lu, Shuai Lu
Summary: In recent years, FLT3 has been identified as an exciting target for AML treatment. However, resistance to FLT3 inhibitors caused by acquired point mutations in the tyrosine kinase domain (TKD) has limited their efficacy. Compound LT-540-717 (32) has been discovered as a potent FLT3 inhibitor with inhibitory activity against multiple acquired FLT3 mutations. It also exhibits antiproliferative activity against FLT3-mutation driven cells and shows potential as a new anti-AML drug.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Sabine Hannes, Rebekka Karlowitz, Sjoerd J. L. van Wijk
Summary: This study demonstrates that the combination of STING and BV6 can effectively induce necroptosis in apoptosis-deficient pancreatic cancer cells, offering potential antitumor effects and implications for new treatment strategies against pancreatic cancer.
CELL DEATH & DISEASE
(2021)
Article
Oncology
Anu Gupta, Jarnail Singh, Alfonso Garcia-Valverde, Cesar Serrano, Daniel L. Flynn, Bryan D. Smith
Summary: The majority of GIST patients develop secondary resistance mutations in KIT after treatment with KIT kinase inhibitors. Tumor heterogeneity and reactivation of the MAPK pathway pose challenges to GIST treatment. Combination therapy of ripretinib with MEK inhibitors shows potential for inducing cytocidal responses in GIST and SM cells.
MOLECULAR CANCER THERAPEUTICS
(2021)
Review
Biochemistry & Molecular Biology
Allyson M. Freedy, Brian B. Liau
Summary: The text highlights how resistance mutations to small molecules have unlocked the potential for discovering new biology, and suggests leveraging emerging technologies to drive basic biology research and drug discovery. By recognizing the role of resistance mutations in biological discovery, new technologies can be harnessed to maximize the potential of small molecules in advancing our understanding of biology and improving human health.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Mingxing Teng, Marlise R. Luskin, Sandra W. Cowan-Jacob, Qiang Ding, Doriano Fabbro, Nathanael S. Gray
Summary: This review discusses the recent progress in the treatment of chronic myeloid leukemia (CML) and highlights the discovery and mechanism of action of allosteric inhibitors. The therapeutic potential of these inhibitors in delaying the development of acquired resistance is also explored. The article emphasizes the importance of understanding the fundamental regulatory mechanisms of kinases and presents key lessons learned from this program.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Rui Cheng, Lixing Xiao, Wenyang Zhou, Xiyun Jin, Zhaochun Xu, Chang Xu, Pingping Wang, Meng Luo, Mengyun Wang, Kexin Ma, Huimin Cao, Yan Huang, Xiaoyu Lin, Fenglan Pang, Yiqun Li, Qinghua Jiang
Summary: This study conducted a pan-cancer analysis of alternative splicing of splicing factors and identified 167 splicing factors with implications in regulating cancer-specific splicing patterns. The findings suggest that alternative splicing of splicing factors may serve as common regulators for alternative splicing in different cancers, highlighting its potential importance in tumorigenesis. Additionally, a splicing-derived neoepitopes database (ASPNs) was developed to provide putative alternative splicing-derived neoepitopes of 16 cancer types.
