- Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants
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The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants. It showed IC50 (half maximal inhibitory concentration) values of 0.010 μM, 0.015 μM, and 0.009 μM against RET-wild-type, RET-V804M, and RET-V804L, respectively. 17d displayed significant anti-viability potencies against various RET-driving tumor cell lines. In a xenograft mouse model of NIH3T3-RET-C634Y, 17d exhibited potent in vivo anti-tumor activity, and no obvious toxicity was observed. Mechanisms of action were also investigated by Western blot and immunohistochemical assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation.
- Yang, Jiao,Chen, Kai,Zhang, Guo,Yang, Qiu-Yuan,Li, Yue-Shan,Huang, Shen-Zhen,Wang, Yan-Lin,Yang, Wei,Jiang, Xiao-Juan,Yan, Heng-Xiu,Zhu, Jing-Qiang,Xiang, Rong,Luo, You-Fu,Li, Wei-Min,Wei, Yu-Quan,Li, Lin-Li,Yang, Sheng-Yong
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- Structural Optimization and Structure-Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6 H-pyrimido[5,4- b][1,4]oxazin-7(8 H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants
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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.
- Bin, Huachao,Huang, Qiao,Li, Linli,Li, Yang,Liu, Yang,Luo, Xinling,Mu, Bo,Nan, Jinshan,Pan, Shulei,Pan, Zhiling,Tian, Chenyu,Wang, Falu,Wang, Tianqi,Yang, Shengyong,Yang, Wei,Zhang, Liting
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p. 2035 - 2058
(2022/02/14)
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- FGFR4 kinase inhibitor, preparation method and uses thereof
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The present invention relates to a compound represented by a formula (I), or a pharmaceutically acceptable salt, a solvate, a polymorph or an isomer thereof, and uses in preparation of drugs for treatment of FGFR4 mediated diseases.
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Paragraph 0244-0245; 0249-0250
(2020/04/17)
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- Pyrazole spleen tyrosine kinase inhibitor as well as preparation method and application thereof
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The invention discloses a pyrazole spleen tyrosine kinase inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and application of the pyrazole spleen tyrosine kinase inhibitor and the pharmaceutical composition in the preparation of drugs for treating Syk-mediated diseases including cancers, inflammatory diseases and the like.
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Paragraph 0453-0456
(2020/12/29)
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- Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase
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Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, 25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren's syndrome.
- Angst, Daniela,Gessier, Fran?ois,Janser, Philipp,Vulpetti, Anna,W?lchli, Rudolf,Beerli, Christian,Littlewood-Evans, Amanda,Dawson, Janet,Nuesslein-Hildesheim, Barbara,Wieczorek, Grazyna,Gutmann, Sascha,Scheufler, Clemens,Hinniger, Alexandra,Zimmerlin, Alfred,Funhoff, Enrico G.,Pulz, Robert,Cenni, Bruno
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p. 5102 - 5118
(2020/06/10)
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- Pyrimidomorpholine derivative, and preparation method and application thereof
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The invention specifically relates to a small molecule compound capable of resisting medullary thyroid carcinoma, acute leukemia and inflammations, and a preparation method and application thereof, belonging to the field of chemical pharmaceuticals. The objective of the invention is to overcome the technical problems of poor selectivity, easy incurrence of drug resistance and toxic and side effectof conventional commercially-available clinical medicines for medullary thyroid carcinoma. The invention provides a pyrimidomorpholine derivative to overcome the above technical problem. The pyrimidomorpholine derivative is mainly characterized in that the position 6 of pyrimidine is substituted, and the structure of the pyrimidomorpholine is as shown in a formula I which is described in the specification. The compound provided by the invention has the advantages of high activity in resisting medullary thyroid carcinoma, low toxic and side effect and capacity of overcoming clinical drug resistance, and has great value in development of medicines for treating medullary thyroid carcinoma.
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Paragraph 0213; 0214; 0215
(2018/07/07)
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