1380917-35-0Relevant articles and documents
The discovery of novel 3-aryl-indazole derivatives as peripherally restricted pan-Trk inhibitors for the treatment of pain
Shirahashi, Hiromitsu,Toriihara, Eisuke,Suenaga, Yoshihito,Yoshida, Hideyuki,Akaogi, Kensuke,Endou, Yukiko,Wakabayashi, Makoto,Takashima, Misato
, p. 2320 - 2326 (2019)
The design, synthesis, and biological evaluation of novel 3-aryl-indazole derivatives as peripherally selective pan-Trk inhibitors are described. Three strategies were used to obtain a potent compound exhibiting low central nervous system (CNS) penetratio
Indazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor
Tomassi, Stefano,Lategahn, Jonas,Engel, Julian,Keul, Marina,Tumbrink, Hannah L.,Ketzer, Julia,Mühlenberg, Thomas,Baumann, Matthias,Schultz-Fademrecht, Carsten,Bauer, Sebastian,Rauh, Daniel
, p. 2361 - 2372 (2017)
The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds. These inhibitors are conformationally less flexible, target gatekeeper mutated drug-resistant EGFR-L858R/T790M, and covalently alkylate Cys797. Western blot analysis, as well as characterization of the binding kinetics and kinase selectivity profiling, substantiates our approach of targeting drug-resistant EGFR-L858R/T790M with inhibitors incorporating the indazole as hinge binder.
INHIBITORS OF CAMKK2 AND USES OF SAME
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Paragraph 0162; 0163, (2020/12/08)
The present disclosure provides compounds suitable for inhibiting CaMKK2. Also provided are compositions and methods of treating diseases associated with CaMKK2.
Design, synthesis, and Structure–Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors
Chan, Shingpan,Ding, Ke,Duan, Yunxin,Tu, Zheng-Chao,Wang, Jie,Zhang, Zhang,Zhu, Sihua
, (2020/07/21)
Neurotrophic receptor tyrosine kinase (NTRK) fusions are oncogenic drivers for a variety of adult and pediatric tumors, validated by the US FDA approval of small molecular Trk inhibitors Larotrectinib (1, LOXO-101) and Entrectinib (2). However, gene mutation mediated resistance becomes a major challenge for Trk inhibitor therapies. Herein, we report the design, synthesis and Structure–Activity Relationship investigation of a series of 3-vinylindazole derivatives as new Trk inhibitors with low nanomolar potencies. A representative compound, 7mb, binds to TrkA/B/C with Kd values of 1.6, 3.1 and 4.9 nM, and suppresses their kinase functions with IC50 values of 1.6, 2.9 and 2.0 nM, respectively, but is obviously less potent for the majority of a panel of 403 wild-type kinases in a KINOMEscan selectivity investigation. The compound also potently suppresses proliferation of a panel of BaF3 cells stably transformed with NTRK fusions with IC50 values in low nM ranges. Additionally, the compound exhibits strong inhibition against the Larotrectinib-resistant cells with NTRK1-G667C or NTRK3-G696A mutations with IC50 values of 0.031 and 0.018 μM, respectively. Although the relatively poor oral bioavailability of 7mb will limit its further development, this compound may be utilized a lead molecule for further structural optimization.
Design, synthesis and biological evaluation of 3,5-dimethylisoxazole and pyridone derivatives as BRD4 inhibitors
Rong, Juan,Feng, Zhan-Zhan,Shi, Yao-Jie,Ren, Jing,Xu, Ying,Wang, Ning-Yu,Xue, Qiang,Liu, Kun-Lin,Zhou, Shu-Yan,Wei, Wei,Yu, Luo-Ting
, (2019/08/20)
Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, has been recognized as an attractive candidate target for the treatment targeting gene transcription in several types of cancers. In this study, two types of novel compounds were designed, synthesized and evaluated as BRD4 inhibitors. Therein, pyridone derivatives were more effective against BRD4 protein and human leukemia cell lines MV4-11. Among them, compounds 11d, 11e and 11f were the most potential ones with IC50 values of 0.55 μM, 0.86 μM and 0.80 μM against BRD4, and exhibited remarkable antiproliferative activities against MV4-11 cells with IC50 values of 0.19 μM, 0.32 μM and 0.12 μM, respectively. Moreover, in western blot assay, compound 11e induced down-regulation of C-Myc, which is a significant downstream gene of BRD4. Cell cycle analysis assay also showed that compound 11e could block MV4-11 cells at G0/G1 phase. Taken together, our results suggested that compound 11e and its derivatives were a class of novel structural potential BRD4 inhibitors and could serve as lead compounds for further exploration.
The discovery of novel 3-(pyrazin-2-yl)-1H-indazoles as potent pan-Pim kinase inhibitors
Wang, Hui-Ling,Cee, Victor J.,Chavez, Frank,Lanman, Brian A.,Reed, Anthony B.,Wu, Bin,Guerrero, Nadia,Lipford, J. Russell,Sastri, Christine,Winston, Jeff,Andrews, Kristin L.,Huang, Xin,Lee, Matthew R.,Mohr, Christopher,Xu, Yang,Zhou, Yihong,Tasker, Andrew S.
, p. 834 - 840 (2015/02/19)
The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.
Synthesis and antimicrobial screening of novel 3, 5-disubstituted indazole derivatives
Padmaja,Yedukondalu,Sridhar,Busi, Siddhardha,Rao, M.V. Basaveswara
, p. 625 - 631 (2013/08/23)
Amine coupling strategy was developed for the synthesis of new indazole derivatives through reaction of 4-(3- (4-hydroxyphenyl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-5-yl) benzoic acid 19 with amines 20a-i. All the newly synthesized compounds were screened for their antimicrobial and antifungal activities. Among the several compounds synthesized (4-(3-(4-hydroxyphenyl)-1H- indol-5-yl)phenyl)(piperazin-1-yl)methanone 2, (4-(3-(4-hydroxyphenyl)- 1Hindazol- 5-yl)phenyl)(4-methylpiperazin-1-yl)methanone 3, 1-(4-(4-(3-(4- hydroxyphenyl)-1H-indol-5-yl) benzoyl) piperazin- 1-yl) ethanone 4 and (4-(3-(4-hydroxyphenyl)-1H-indol-5-yl) phenyl)(pyrrolidin-1-yl)methanone 9 showed potential activities against a variety of bacterial and fungal strains.
