1340334-65-7Relevant academic research and scientific papers
Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer
Yang, Huali,Wang, Xiaobing,Wang, Cheng,Yin, Fucheng,Qu, Lailiang,Shi, Cunjian,Zhao, Jinhua,Li, Shang,Ji, Limei,Peng, Wan,Luo, Heng,Cheng, Maosheng,Kong, Lingyi
, (2020/12/15)
NUAK, the member of AMPK (AMP-activated protein kinase) family of protein kinases, is phosphorylated and activated by the LKB1 (liver kinase B1) tumor suppressor protein kinase. Recent work has indicated that NUAK1 is a key component of the antioxidant stress response pathway, and the inhibition of NUAK1 will suppress the growth and survival of colorectal tumors. As a promising target for anticancer drugs, few inhibitors of NUAK were developed. With this goal in mind, based on NUAK inhibitor WZ4003, a series of derivatives has been synthesized and evaluated for anticancer activity. Compound 9q, a derivative of WZ4003 by removing a methoxy group, was found to be the most potential one with stronger inhibitory against NUAK1/2 enzyme activity, tumor cell proliferation and inducing apoptosis of tumor cells. By in vivo efficacy evaluations of colorectal SW480 xenografts, 9q suppresses tumor growth more effectively with an excellent safety profile in vivo and is therefore seen as a suitable candidate for further investigation.
Discovery and structure ? activity relationship exploration of pyrazolo[1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors
Chen, Yun,Bai, Gang,Li, Yan,Ning, Yi,Cao, Sufen,Zhou, Jinpei,Ding, Jian,Zhang, Huibin,Xie, Hua,Duan, Wenhu
, (2021/09/28)
Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately 25% of all acute myeloid leukemia (AML) cases and confer a poor prognosis. Optimization of the screening hit 1 from our in-house compound library led to the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives as potent and selective FLT3-ITD inhibitors. Compounds 17 and 19 displayed potent FLT3-ITD activities both with IC50 values of 0.4 nM and excellent antiproliferative activities against AML cell lines. Especially, compounds 17 and 19 inhibited the quizartinib resistance- conferring mutations, FLT3D835Y, both with IC50 values of 0.3 nM. Moreover, western blot analysis indicated that compounds 17 and 19 potently inhibited the phosphorylation of FLT3 and attenuated downstream signaling in AML cells. These results indicated that pyrazolo[1,5-a]pyrimidine derivatives could be promising FLT3-ITD inhibitors for the treatment AML.
Design, synthesis and biological evaluation of 2-arylaminopyrimidine derivatives bearing 1,3,8-triazaspiro[4,5]decan-4-one or piperidine-3-carboxamide moiety as novel Type-I1/2 ALK inhibitors
Gong, Ping,Guo, Ming,Liu, Sicong,Miao, Xiuqi,Xing, Lingyun,Yin, Shiliang,Zhai, Xin,Zhang, Dajun,Zhang, Hong
, (2019/12/26)
Aiming to develop novel Type-I1/2 inhibitors of ALK to overcome extensive resistance mutations, especially the L1196M mutation surrounding the ATP pocket, two series of 2-arylaminopyrimidine derivatives (11a-f and 22a-t) were designed based on scaffold hopping. The extensive structural elaboration discovered compound 22o which possessed excellent IC50 values of 0.06 and 0.23 μM against ALK-positive Karpas299 and H2228 cell lines, respectively. Meanwhile, 22o displayed encouraging inhibitory potency in the ALKWT (2.5 nM) and ALKL1196M (6.5 nM) enzymatic assays. Furthermore, the AO/EB and Hoechst 33258 assays illustrated 22o could induce cell apoptosis in a dose-dependent manner. Eventually, the molecular docking of 22o with ALK clearly presented the vital interactions within the active site, which was in accordance with Type-I1/2 inhibitor binding mode.
Catalyst-Directed Chemoselective Double Amination of Bromo-chloro(hetero)arenes: A Synthetic Route toward Advanced Amino-aniline Intermediates
Mikhailine, Alexandre A.,Grasa Mannino, Gabriela A.,Colacot, Thomas J.
supporting information, p. 2301 - 2305 (2018/04/30)
A chemoselective sequential one-pot coupling protocol was developed for preparing several amino-anilines in high yield as building blocks for active pharmaceutical ingredients (APIs). Site (Cl vs Br on electrophile) and nucleophile (amine vs imine) selectivity is dictated by the catalyst employed. A Pd-crotyl(t-BuXPhos) precatalyst selectively coupled the Ar-Br of the polyhaloarene with benzophenone imine, even in the presence of a secondary amine, while Pd-based RuPhos or (BINAP)Pd(allyl)Cl coupled the Ar-Cl site with secondary amines.
