Discovery of the cancer cell selective dual acting anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131)
摘要:
Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI(50) 1.5 mu M). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day. (C) 2018 Elsevier Masson SAS. All rights reserved.
A compound of formula I, wherein the compound of formula I has the structure: wherein R1 to R5, Y, L, Z and X1 to X7 have meanings given in the description, said compounds having utility in the treatment of hyperproliferative disease.
A compound of formula I, wherein the compound of formula I has the structure: wherein R1 to R5, Y, L, Z and X1 to X7 have meanings given in the description, said compounds having utility in the treatment of hyperproliferative disease.
一种式 I 的化合物,其中式 I 的化合物具有如下结构: 其中 R1 至 R5、Y、L、Z 和 X1 至 X7 的含义如描述中所给出,所述化合物在治疗过度增殖性疾病中具有实用性。
(Z)-2-(1H-INDOL-3-YL)-3-(ISOQUINOLIN-5-YL)ACRYLONITRILE DERIVATIVES AND RELATED COMPOUNDS WITH LYSOSOME INHIBITORY AND ANTI-MITOTIC ACTIVITY FOR TREATING HYPERPROLIFERATIVE DISEASES
申请人:National University of Singapore
公开号:EP3307724B1
公开(公告)日:2020-06-10
SELECTIVE ANTI-CANCER COMPOUNDS
申请人:National University of Singapore
公开号:EP3307724A1
公开(公告)日:2018-04-18
ANTI-CANCER COMPOUNDS AND USES THEREOF
申请人:NATIONAL UNIVERSITY OF SINGAPORE
公开号:US20190350964A1
公开(公告)日:2019-11-21
Compounds and their use in modulating the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways to protect normal cells in scenarios such as chemotherapy to kill cancer cells are provided. The compounds inhibit phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) and/or increase phosphoinositide 3-kinase-interacting protein 1 (PIK31P1). Also provided are methods for identifying such compounds, methods of treatment using same and other uses.