Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation

Yan, Wei; Zhang, Lingtian; Lv, Fengping; Moccia, Marialuisa; Carlomagno, Francesca; Landry, Christophe; Santoro, Massimo; Gosselet, Fabien; Frett, Brendan; Li, Hongyu

doi:10.1016/j.ejmech.2021.113265

Cited by 23 publications

(10 citation statements)

References 43 publications

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“…Discovery of Trks small-molecule inhibitors has attracted much attention in pharmaceutical companies and academic communities in the past decade. A number of Trks small-molecule inhibitors have been reported. − Representative Trks inhibitors are displayed in Figure , including larotrectinib (LOXO101), entrectinib (RXDX101), belizatinib, milciclib, cabozantinib, and altiratinib. Among them, larotrectinib and entrectinib have been approved by U.S. Food and Drug Administration in November 2018 and August 2019, respectively, to treat adult and pediatric patients with solid tumors containing NTRK gene fusion-positive. − Despite the good progress in the development of Trks-targeting anticancer drugs, acquired resistance soon emerged in most patients.…”

Section: Introductionmentioning

confidence: 99%

Structural Optimization and Structure–Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants

et al. 2022

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Tropomyosin receptor kinases (TrkA, TrkB, and TrkC) are attractive therapeutic targets for multiple cancers. Two first-generation small-molecule Trks inhibitors, larotrectinib and entrectinib, have just been approved to use clinically. However, the drug-resistance mutations of Trks have already emerged, which calls for new-generation Trks inhibitors. Herein, we report the structural optimization and structure–activity relationship studies of 6,6-dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one derivatives as a new class of pan-Trk inhibitors. The prioritized compound 11g exhibited low nanomolar IC50 values against TrkA, TrkB, and TrkC and various drug-resistant mutants. It also showed good kinase selectivity. 11g displayed excellent in vitro antitumor activity and strongly suppressed Trk-mediated signaling pathways in intact cells. In in vivo studies, compound 11g exhibited good antitumor activity in BaF3-TEL-TrkA and BaF3-TEL-TrkCG623R allograft mouse models without exhibiting apparent toxicity. Collectively, 11g could be a promising lead compound for drug discovery targeting Trks and deserves further investigation.

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Section: Introductionmentioning

confidence: 99%

Structural Optimization and Structure–Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants

et al. 2022

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“…NGF and its receptors are expressed in lung cancer, and this autocrine stimulus plays an important role in the development of malignant tumors and is associated with low tumor survival rates (Prakash et al, 2010). Kim and other studies have shown that TRKA inhibitors have a significant inhibitory effect on the proliferation of human lung cancer cells but have a low inhibitory effect on normal MRC5 cells (Yan et al, 2021). In summary, it is very important to identify specific HERV-K sites related to specific diseases, especially HERV-K polymorphic sites, which may affect the expression profile of the virus in different individuals and the regulation of host genes.…”

Section: (Continued)mentioning

confidence: 99%

Significant Upregulation of HERV-K (HML-2) Transcription Levels in Human Lung Cancer and Cancer Cells

Yang

Guo

et al. 2022

Front. Microbiol.

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Lung cancer is the second most common cancer worldwide and the leading cause of cancer death in the world. Therefore, there is an urgent need to develop new and effective biomarkers for diagnosis and treatment. Under this circumstance, human endogenous retroviruses (HERVs) were recently introduced as novel biomarkers for cancer diagnosis. This study focused on the correlation between lung cancer and HERV-K (HML-2) transcription levels. At the cellular level, different types of lung cancer cells and human normal lung epithelial cells were used to analyze the transcription levels of the HERV-K (HML-2) gag, pol, and env genes by RT–qPCR. At the level of lung cancer patients, blood samples with background information from 734 lung cancer patients and 96 healthy persons were collected to analyze the transcription levels of HERV-K (HML-2) gag, pol, and env genes. The results showed that the transcriptional levels of the HERV-K (HML-2) gag, pol, and env genes in lung cancer cells and lung cancer patient blood samples were significantly higher than those in the healthy controls, which was also verified by RNAScope ISH technology. In addition, we also found that there was a correlation between the abnormal transcription levels of HERV-K (HML-2) genes in lung cancer patients and the clinicopathological parameters of lung cancer. We also identified the distribution locations of the gag, pol, and env primer sequences on each chromosome and analyzed the function of these loci. In conclusion, HERV-K (HML-2) genes may be a potential biomarker for the diagnosis of lung cancer.

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“…The blood-brain barrier (BBB) permeability studies were performed using the in vitro human BBB model previously described and detailed 32 . After infant's parents signed informed consents, endothelial cells were isolated and differentiated from cord blood CD34 +hematopoietic stem cells according to the protocol described by Pedroso et al 33 to predict molecule toxicity and passage to the CNS [34][35][36][37] .…”

Section: Human Blood-brain Barrier Model Setting Upmentioning

confidence: 99%

A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning

Silva¹,

Probst

Landry

et al. 2022

J. Med. Chem.

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Recent events demonstrated that organophosphorus nerve agents are a serious threat for civilian and military populations. The current therapy includes a pyridinium aldoxime reactivator to restore the enzymatic activity of acetylcholinesterase located in the central nervous system and neuro-muscular junctions. One major drawback of these charged acetylcholinesterase reactivators is their poor ability to cross the blood-brain barrier to reach the centrally inhibited enzymes. Many strategies have been evaluated over the years to overcome this weakness. In this study, we propose to evaluate glucoconjugated oximes devoid of permanent charge as potential central nervous system reactivators. We determined their in vitro reactivation efficacy on organophosphorus inhibited human acetylcholinesterase and the crystal structure of two compounds in complex with the enzyme. We also determined their protective index on intoxicated mice as well as their pharmacokinetics. In order to gain a fine understanding of our compounds trafficking through the blood-brain barrier, we evaluated the endothelial 2 permeability coefficients of our molecules with a human in vitro model. This study shed light on the structural restrains of new sugar oximes designed to reach the central nervous system through the active glucose transporter located at the blood-brain barrier.

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Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation

Cited by 23 publications

References 43 publications

Structural Optimization and Structure–Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants

Structural Optimization and Structure–Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants

Significant Upregulation of HERV-K (HML-2) Transcription Levels in Human Lung Cancer and Cancer Cells

A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning

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