1197159-91-3Relevant articles and documents
5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class i PI3K/mTOR Inhibitor as Clinical Candidate in Oncology
Beaufils, Florent,Cmiljanovic, Natasa,Cmiljanovic, Vladimir,Bohnacker, Thomas,Melone, Anna,Marone, Romina,Jackson, Eileen,Zhang, Xuxiao,Sele, Alexander,Borsari, Chiara,Mestan, Jürgen,Hebeisen, Paul,Hillmann, Petra,Giese, Bernd,Zvelebil, Marketa,Fabbro, Doriano,Williams, Roger L.,Rageot, Denise,Wymann, Matthias P.
, p. 7524 - 7538 (2017)
Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
New and Practical Synthesis of Gedatolisib
Liu, Xiangyu,Zhu, Guoqing,Li, Lingai,Liu, Yaowei,Wang, Feng,Song, Xiaoping,Mao, Yongjun
, p. 62 - 66 (2018)
A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.
Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer
Wu, Chun-Feng,Wang, Qing-Chen,Chen, Rui,Zhou, Hai-Ling,Wu, Ting-Ting,Du, Yao,Zhang, Na-Na,Zhang, Hui-Min,Fan, Zu-Yan,Wang, Li-Li,Hu, Chu-Jiao,Sang, Zhi-Pei,Li, Hong-Liang,Wang, Ling,Tang, Lei,Zhang, Ji-Quan
, (2022/01/03)
The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l-prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 μM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.
Diarylurea PI3Kalpha/mTOR double-target inhibitor and pharmaceutical composition, and application of inhibitor and pharmaceutical composition
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Paragraph 0143; 0147-0149, (2021/07/01)
The invention discloses a diarylurea PI3Kalpha/mTOR double-target inhibitor as well as a pharmaceutical composition, and application of the diarylurea PI3K alpha/mTOR double-target inhibitor and the pharmaceutical composition. The diarylurea PI3Kalpha/mTOR double-target inhibitor comprises a substituted triazine compound with a general formula (I) described in the specification, and a stereoisomer, a hydrate or a pharmaceutically acceptable salt thereof. The diarylurea PI3Kalpha/mTOR double-target inhibitor provided by the invention and the pharmaceutical composition containing the diarylurea PI3K alpha/mTOR double-target inhibitor can be used for inhibiting PI3Kalpha/mTOR double kinase and proliferative diseases caused by the PI3Kalpha/mTOR double kinase, and an inhibitor with better effectiveness and selectivity can be provided for treatment of the PI3Kalpha/mTOR double-kinase-induced proliferative diseases.
Substituted benzimidazole PI3K[alpha]/mTOR double-target inhibitor as well as pharmaceutical composition and application thereof
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, (2020/06/05)
The invention discloses a substituted benzimidazole PI3K[alpha]/mTOR double kinase inhibitor as well as a pharmaceutical composition and application thereof. The substituted benzimidazole PI3K[alpha]/mTOR double kinase inhibitor comprises a compound shown in a general formula (I) or a stereoisomer, a geometrical isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof,the substituted benzimidazole PI3K[alpha]/mTOR double kinase inhibitor and the pharmaceutical composition thereof provided by the invention can be used for inhibiting PI3K[alpha]/mTOR double kinase and acting on proliferative diseases related to the PI3K[alpha]/mTOR double kinase; and an inhibitor with a novel structure is provided for treating proliferative diseases with PI3K[alpha]/mTOR doublekinase.
HSP90-TARGETING CONJUGATES AND FORMULATIONS THEREOF
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Paragraph 0309; 0315, (2020/05/06)
Conjugates of an active agent attached to a targeting moiety, such as an HSP90 binding moiety, via a linker, and particles comprising such conjugates have been designed. Such conjugates and particles can provide improved temporospatial delivery of the active agent, improved biodistribution and penetration in tumor, and/or decreased toxicity. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer.
PI3Kalpha/mTOR bikinase inhibitor as well as pharmaceutical composition and application thereof
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, (2018/07/30)
The invention discloses a PI3Kalpha/mTOR bikinase inhibitor as well as a pharmaceutical composition and application thereof. The PI3Kalpha/mTOR bikinase inhibitor is prepared from a compound shown ina general formula (I), or a stereoisomer, a geometric isomeride, a hydrate, a solvate, or pharmaceutically acceptable salt or a prodrug: (the formula (1) is shown in the description.) The invention provides the PI3Kalpha/mTOR bikinase inhibitor and the pharmaceutical composition thereof for inhibiting PI3Kalpha/mTOR bikinase and proliferation diseases having a PI3Kalpha/mTOR bikinase effect; moreover, a more effective and higher selectivity inhibitor can be provided for treating the proliferation diseases having the PI3Kalpha/mTOR bikinase effect.
Gedatolisib intermediates for preparation of (by machine translation)
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, (2018/09/14)
The invention belongs to the organic synthesis and bulk drug intermediate preparation field, in particular to a method for preparing Gedatolisib, key intermediate and a key intermediate in the preparation method. The nitrobenzene nitrile and dicyanodiamine polyisobutylene triazine cyclization, morpholine link guan huan, hydrogenation of nitro reduction to obtain 4 - (4, 6 - II morpholino - 1, 3, 5 - triazine - 2 - yl) aniline; 4 - oxo-piperidine - 1 - carboxylic acid tert-butyl and dimethylamine salt by addition, de-Boc protecting group, amide, hydrogenation of nitro reduction to get new compounds (4 - aminophenyl) (4 - (dimethyl amino) piperidine - 1 - yl) methyl ketone; adopts the one-pot synthesis, (4, 6 - II morpholino - 1, 3, 5 - triazine - 2 - yl) aniline and chloromethane acid ester after the reaction, then adding (4 - aminophenyl) (4 - (dimethyl amino) piperidine - 1 - yl) methanone, to finally obtain the Gedatolisib. This preparation method has the advantages of easy availability of raw materials, process is simple, easy to operate, high yield and low cost and the like. (by machine translation)
TRIAZINE COMPOUNDS AS PI3 KINASE AND MTOR INHIBITORS
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Paragraph 0929, (2017/05/19)
Compounds of formula I wherein: R1 is and R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.
Discovery of 1-(3-aryl-4-chlorophenyl)-3-(p-aryl)urea derivatives against breast cancer by inhibiting PI3K/Akt/mTOR and Hedgehog signalings
Li, Wenlu,Sun, Qinsheng,Song, Lu,Gao, Chunmei,Liu, Feng,Chen, Yuzong,Jiang, Yuyang
, p. 721 - 733 (2017/11/01)
PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design. Several compounds displayed excellent antiproliferative activities against several breast cancer cell lines, including triple-negative breast cancer (TNBC) MDA-MB-231 cell. Further mechanistic studies demonstrated that the representative compound 9i could inhibit both PI3K/Akt/mTOR and hedgehog (Hh) signalings by inhibiting the phosphorylation of S6K and Akt as well as decreasing the SAG elevated expression of Gli1. Compound 9i could also induce apoptosis remarkably in T47D and MDA-MB-231 cells. In the transwell assay, 9i showed significant inhibition on the migration of MDA-MB-231.
