- Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design
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A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, A12, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure-activity relationship of compound A12, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.
- Dong, Xiaowu,Zhan, Wenhu,Zhao, Mengting,Che, Jinxin,Dai, Xiaoyang,Wu, Yizhe,Xu, Lei,Zhou, Yubo,Zhao, Yanmei,Tian, Tian,Cheng, Gang,Jin, Zegao,Li, Jia,Shao, Yanfei,He, Qiaojun,Yang, Bo,Weng, Qinjie,Hu, Yongzhou
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supporting information
p. 7264 - 7288
(2019/08/20)
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- SUBSTITUTED NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVES, PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME AND APPLICATIONS OF ANTITUMOR THEREOF
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Disclosed are new substituted nitrogen-containing heterocyclic derivatives represented by formula (I) as AKT inhibitors, optical isomers, pharmaceutically acceptable salts or solvates thereof, wherein the definition of R1, R2, R3, R4, R5, R6, ring A, ring
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Paragraph 0314
(2017/02/28)
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- Substituted pyrazol ring derivative and application thereof
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The invention discloses a substituted pyrazol ring derivative. The substituted pyrazol ring derivative is shown as the general formula I. The invention further provides an optical isomer or salt acceptable agriculturally of the substituted pyrazol ring derivative. The substituted pyrazol ring derivative, the optical isomer or the salt acceptable agriculturally can be used for preparing bactericides (including agricultural and gardening bactericides), and therefore prevention and control over agricultural and gardening fungi are achieved.
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Paragraph 0091; 0092; 0097; 0098
(2016/10/09)
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- AFURESERTIB: Protein kinase B (PKB) inhibitor Oncolytic
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The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays key roles in cellular proliferation and survival. Mutations and alterations in this signal transduction pathway have been described in a variety of solid and hematopoietic malignancies, which may contribute to perpetuation of the disease in a number of ways. Increasing interest in targeting particular facets of this signaling cascade has led to the development of a number of novel anticancer agents, including afuresertib (GSK-2110183), an orally bioavailable pan-inhibitor of the RAC-alpha serine/threonine protein kinase, also referred to as protein kinase B or proto-oncogene c-Akt. The present review summarizes the preclinical and pharmacological aspects of afuresertib and early clinical experience.
- Conkel,Benson
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p. 541 - 546
(2014/12/11)
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