885271-25-0Relevant articles and documents
INHIBITORS OF ENL/AF9 YEATS
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Paragraph 00153-00154, (2021/06/26)
Methods and compositions for treating leukemia are disclosed. Acylated 6-aminoindoles, acylated 6-aminopyrrolopyridines and acylated 3-aminopyrrolo[3,2-c]pyridazines of the following formula inhibit ENL/AF9 YEATS and are therefore useful for treating leukemia.
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.
NOVEL SUBSTITUTED 3-INDOLE AND 3-INDAZOLE COMPOUNDS AS PHOSPHODIESTERASE INHIBITORS
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Page/Page column 76, (2019/01/10)
The invention relates to novel 3-indole and 3-indazole compounds characterized in that the compound has general formula (I) in which the chemical groupings, substituents. variables and indices are as defined in the description, and to their use as medicam
