956034-04-1Relevant articles and documents
Discovery of novel and potent PARP/PI3K dual inhibitors for the treatment of cancer
Wu, Zhengyang,Bai, Ying,Jin, Jiaming,Jiang, Teng,Shen, Hui,Ju, Qiurong,Zhu, Qihua,Xu, Yungen
, (2021/03/19)
PARP inhibitors have achieved great success in cancers with BRCA mutations, but only a small portion of patients carry BRCA mutations, which results in their narrow indication spectrum. Recently, emerging evidence has demonstrated that combinations of PARP and PI3K inhibitors could evoke unanticipated synergistic effects in various cancers, even including BRCA-proficient ones. In this work, a series of PARP/PI3K dual inhibitors were designed, synthesized, and evaluated for their biological activities. It was found that compounds 9a and 23a exhibited excellent inhibitory activities against PARP-1 (9a: IC50 = 1.57 nM, 23a: IC50 = 0.91 nM) and PI3Kα (9a: IC50 = 2.0 nM, 23a: IC50 = 1.5 nM), and showed promising antiproliferative activities against both BRCA-deficient (HCT-116, HCC-1937) and BRCA-proficient (SW620, MDA-MB-231/468) tumor cells. 9a and 23a also exhibited considerable in vivo antitumor efficacy in an MDA-MB-468 xenograft mouse model, with TGI values of 56.39% and 48.77%, respectively. Additionally, 23a possessed promising profiles including high kinase selectivity and low cardiotoxicity. Overall, this work indicates 9a and 23a might be potential PARP/PI3K dual inhibitors for cancer therapy and deserve further research.
Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors
Srimongkolpithak, Nitipol,Sundriyal, Sandeep,Li, Fengling,Vedadi, Masoud,Fuchter, Matthew J.
supporting information, p. 1821 - 1828 (2015/01/08)
G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemotypes for substrate competitive inhibitors of G9a, we have designed and synthesised a range of heterocyclic scaffolds, and investigated their ability to inhibit G9a. These studies have led to improved understanding of the key pharmacophoric features of BIX-01294 and the identification of a new core quinoline inhibitory scaffold, which retains excellent potency and high selectivity. Molecular docking was carried out to explain the observed in vitro data. This journal is
Rational design of phosphoinositide 3-kinase inhibitors that exhibit selectivity over the phosphoinositide 3-kinase isoform
Heffron, Timothy P.,Wei, Binqing,Olivero, Alan,Staben, Steven T.,Tsui, Vickie,Do, Steven,Dotson, Jennafer,Folkes, Adrian J.,Goldsmith, Paul,Goldsmith, Richard,Gunzner, Janet,Lesnick, John,Lewis, Cristina,Mathieu, Simon,Nonomiya, Jim,Shuttleworth, Stephen,Sutherlin, Daniel P.,Wan, Nan Chi,Wang, Shumei,Wiesmann, Christian,Zhu, Bing-Yan
experimental part, p. 7815 - 7833 (2012/01/05)
Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3K has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3K vs PI3K selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3K that is not attained with the corresponding Lys777 of PI3K. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.
