Design, Synthesis, and Biological Evaluation of Imidazo[1,2- a]pyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors

Ya'Nan Yu; Yuqiao Han; Fupo Zhang; Zhenmei Gao; Tong Zhu; Suzhen Dong; Mingliang Ma

doi:10.1021/acs.jmedchem.9b01736

Design, Synthesis, and Biological Evaluation of Imidazo[1,2- a]pyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors

Ya'Nan Yu
, Yuqiao Han
, Fupo Zhang
, Zhenmei Gao
, Tong Zhu
, Suzhen Dong^*
, Mingliang Ma

^*Corresponding author for this work

School of Chemistry and Molecular Engineering

East China Normal University

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.

Original language	English
Pages (from-to)	3028-3046
Number of pages	19
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	6
DOIs	https://doi.org/10.1021/acs.jmedchem.9b01736
State	Published - 26 Mar 2020

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title = "Design, Synthesis, and Biological Evaluation of Imidazo[1,2- a]pyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors",

abstract = "PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.",

author = "Ya'Nan Yu and Yuqiao Han and Fupo Zhang and Zhenmei Gao and Tong Zhu and Suzhen Dong and Mingliang Ma",

note = "Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = mar,

day = "26",

doi = "10.1021/acs.jmedchem.9b01736",

language = "英语",

volume = "63",

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T1 - Design, Synthesis, and Biological Evaluation of Imidazo[1,2- a]pyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors

AU - Yu, Ya'Nan

AU - Han, Yuqiao

AU - Zhang, Fupo

AU - Gao, Zhenmei

AU - Zhu, Tong

AU - Dong, Suzhen

AU - Ma, Mingliang

PY - 2020/3/26

Y1 - 2020/3/26

N2 - PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.

AB - PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.

UR - https://www.scopus.com/pages/publications/85082542396

U2 - 10.1021/acs.jmedchem.9b01736

DO - 10.1021/acs.jmedchem.9b01736

M3 - 文章

C2 - 32069401

AN - SCOPUS:85082542396

SN - 0022-2623

VL - 63

SP - 3028

EP - 3046

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 6

ER -

Design, Synthesis, and Biological Evaluation of Imidazo[1,2- a]pyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors

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