- Discovery of novel and potent PARP/PI3K dual inhibitors for the treatment of cancer
-
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.
- Wu, Zhengyang,Bai, Ying,Jin, Jiaming,Jiang, Teng,Shen, Hui,Ju, Qiurong,Zhu, Qihua,Xu, Yungen
-
-
- Piperazinone substitute or derivative thereof, preparation method and application thereof, and pharmaceutical composition
-
The invention relates to a piperazinone substitute or a derivative thereof, a preparation method and application thereof, and a pharmaceutical composition, and belongs to the technical field of anti-tumor drugs. The invention designs a piperazinone substituted heterocyclic small molecule compound. The compound shows good affinity to PI3K delta, and the compound can down-regulate the activity of a PI3K pathway in tumor cells, so that the compound shows good inhibitory activity to PI3K delta dependent tumors, and is expected to be used as one of components of a pharmaceutical preparation for treatment of different tumors. The preparation method of the piperazinone substitute is simple and convenient, and the yield is relatively high.
- -
-
Paragraph 0132; 0143; 0156; 0166; 0169-0172
(2021/06/09)
-
- PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof
-
The invention discloses a PARP-1/PI3K double-target inhibitor or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. According to the invention, the single active component can play a dual inhibition role on PARP-1 and PI3K, so that the dosage is reduced, the treatment effect is improved, and the toxic and side effects are reduced; and the dual inhibition effect on PARP-1 and PI3K is significant, the IC50 value of each target does not exceed 1.0 [mu]M, and the drug using the PARP-1/PI3K double-target inhibitor as the active component can be used for treating a variety of cancers or tumors related to PARP-1 and/or PI3K.
- -
-
Paragraph 0157; 0165-0167; 0191; 0198-0200
(2021/07/01)
-
- COMBINATION THERAPY WITH A PHOSPHOINOSITIDE 3-KINASE INHIBITOR WITH A ZINC BINDING MOIETY
-
The invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an acyl group; and (b) a PD-1 signaling inhibitor; wherein the compound of Formula I or pharmaceutically acceptable salt thereof and the PD-1 signaling inhibitor are administered in amounts which in combination are therapeutically effective. The invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, a PD-1 signaling inhibitor and a pharmaceutically acceptable carrier or excipient.
- -
-
Paragraph 0087; 0104
(2020/04/09)
-
- Design, synthesis and biological evaluation of thieno[3,2-d]pyrimidine derivatives containing aroyl hydrazone or aryl hydrazide moieties for PI3K and mTOR dual inhibition
-
Recently, PI3K and mTOR have been regarded as promising targets for cancer treatment. Herein, we designed and synthesized four series of novel thieno[3,2-d]pyrimidine derivatives that containing aroyl hydrazone or aryl hydrazide moieties. These derivatives act as PI3K/mTOR dual inhibitors, suggesting that they can be used as cancer therapeutic agents. All compounds were tested for anti-proliferative activity against four cancer cell lines. The structure-activity relationship (SAR) studies were conducted by varying the moieties at the C-6 and C-2 positions of the thieno[3,2-d]pyrimidine core. It indicated that aryl hydrazide at C-6 position and 2-aminopyrimidine at C-2 position are optimal fragments. Compound 18b showed the most potent in vitro activity (PI3Kα IC50 = 0.46 nM, mTOR IC50 = 12 nM), as well as good inhibition against PC-3 (human prostate cancer), HCT-116 (human colorectal cancer), A549 (human lung adenocarcinoma) and MDA-MB-231 (human breast cancer) cell lines. Furthermore, Annexin-V and propidium iodide (PI) double staining confirmed that 18b induces apoptosis in cytotoxic HCT-116 cells. Moreover, the influence of 18b on cell cycle distribution was assessed on the HCT-116 cell line, and a cell cycle arrest was observed at the G1/S phases.
- Dong, Jiawen,Fu, Siyu,Han, Yufei,Hou, Yunlei,Jiang, Jia,Qin, Mingze,Tian, Ye,Wang, Ruxin,Zhao, Yanfang
-
-
- Preparation method of thienopyrimidine compounds and application thereof
-
The invention relates to thienopyrimidine derivatives as shown in a general formula I, pharmaceutically acceptable salts or prodrugs and a preparation method thereof, which belong to the technical field of medicinal chemistry. In the general formula I, substituent groups L and R2 have meanings given in the specification. The invention also relates to a compound shown in the general formula I, which has a strong effect of inhibiting PI3K. The invention also relates to an application of the compounds and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparation of drugs fortreating and/or preventing diseases caused by abnormal high expression of PI3K, especially the application in preparation of drugs for treating and/or preventing cancers.
- -
-
Paragraph 0057; 0062-0063
(2020/05/05)
-
- Design, synthesis and biological evaluation of novel 2,4-bismorpholinothieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives as potent antitumor agents
-
To develop novel therapeutic agents with anticancer activities, two series of novel 2,4-bismorpholinyl-thieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives were designed, synthesized and evaluated for their biological activities. Among them, compound A12 showed the most potent antitumor activities against HCT116, PC-3, MCF-7, A549 and MDA-MB-231 cell lines with IC50 values of 3.24 μM, 14.37 μM, 7.39 μM, 7.10 μM, and 16.85 μM, respectively. Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound A12. The results showed that compound A12 obviously inhibited the proliferation of A549 cell lines and decreased mitochondrial membrane potential, which led to the apoptosis of cancer cells and suppressed the migration of tumor cells.
- Ye, Tianyu,Han, Yufei,Wang, Ruxin,Yan, Pingzhen,Chen, Shaowei,Hou, Yunlei,Zhao, Yanfang
-
-
- Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors
-
Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
- Hu, Rong,Liu, Zhi-Hao,Wang, Ning-Yu,Wang, Wan-Li,Xu, Ying,Yu, Luo-Ting,Zhu, Yong-Xia,Zuo, Wei-Qiong
-
supporting information
(2020/08/14)
-
- COMPOUNDS AND THERAPEUTIC USES THEREOF
-
The invention relates to compounds, pharmaceutical compositions and methods useful for treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune disease, diseases associated with over production
- -
-
Paragraph 0192
(2019/06/23)
-
- Design, synthesis, and biological evaluation of novel thienopyrimidine derivatives as PI3Kα inhibitors
-
Three series of novel thienopyrimidine derivatives 9a-l, 15a-l, and 18a-h were designed and synthesized, and their IC50 values against four cancer cell lines HepG-2, A549, PC-3, and MCF-7 were evaluated. Most compounds show moderate cytotoxicity against the tested cancer cell lines. The most promising compound 9a showed moderate activity with IC50 values of 12.32 ± 0.96, 11.30 ± 1.19, 14.69 ± 1.32, and 9.80 ± 0.93 μM, respectively. The inhibitory activities of compounds 9a and 15a against PI3Kα and mTOR kinase were further evaluated. Compound 9a exhibited PI3Kα kinase inhibitory activity with IC50 of 9.47 ± 0.63 μM. In addition, docking studies of compounds 9a and 15a were also investigated.
- Yu, Lide,Wang, Qinqin,Wang, Caolin,Zhang, Binliang,Yang, Zunhua,Fang, Yuanying,Zhu, Wufu,Zheng, Pengwu
-
-
- Design, synthesis, and biological evaluation of thieno[3,2-d]pyrimidine derivatives as potential simplified phosphatidylinositol 3-kinase alpha inhibitors
-
A series of thieno[3,2-d]pyrimidine derivatives as phosphatidylinositol 3-kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21. Determination of a co-crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments.
- Yang, Xiuyan,Deng, Meng,Zhang, Xi,Wang, Yi,Song, Kun,Cong, Ruan,Meng, Linghua,Zhang, Jian
-
p. 2013 - 2022
(2019/11/03)
-
- COMBINATION THERAPY WITH A PHOSPHOINOSITIDE 3-KINASE INHIBITOR WITH A ZINC BINDING MOIETY
-
The invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an acyl group; and (b) a BCL-2 inhibitor; wherein the compound of Formula I or pharmaceutically acceptable salt thereof and a BCL-2 inhibitor are administered in amounts which in combination are therapeutically effective. The invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, a BCL-2 inhibitor and a pharmaceutically acceptable carrier or excipient.
- -
-
Page/Page column 25; 30; 31
(2018/05/24)
-
- Synthesis and biological evaluation of 2,6-disubstituted-9H-purine, 2,4-disubstitued-thieno[3,2-d]pyrimidine and -7H-pyrrolo[2,3-d]pyrimidine analogues as novel CHK1 inhibitors
-
Checkpoint kinase 1 (CHK1) inhibitors can potentiate the effectiveness of deoxyribonucleic acid (DNA) damaging agents in the treatment of cancer. A novel series of 2,6-disubstituted-9H-purine (3a-p, 5a and 5b), 2,4-disubstituted-thieno[3,2-d]pyrimidine (8
- Tian, Chao,Han, Zifei,Li, Yuanxin,Wang, Meng,Yang, Jiajia,Wang, Xiaowei,Zhang, Zhili,Liu, Junyi
-
p. 836 - 848
(2018/04/25)
-
- FUSED PYRIMIDINES AS ISOFORM SELECTIVE PHOSPHOINOSITIDE-3-KINASE-ALPHA INHIBITORS AND PROCESS FOR PREPARATION THEREOF
-
The present invention relates to fused pyrimidines of formulae I and II wherein, R1, R2 are as herein described. The present invention particularly relates to isoform selective PI3Kα inhibition and their medicinal use as anticancer agents.
- -
-
Page/Page column 17
(2017/06/23)
-
- Thiophene pyrimidines and preparation and its preparation method and application
-
The invention discloses a pyrantel compound and preparation, as well as a preparation method and application of the pyrantel compound and preparation, belonging to the technical field of chemical medicines and preparations thereof. According to the pyrantel compound or pharmaceutically acceptable salt thereof, HDAC (histone deacetylase)/PI3K (phosphatidylinositide 3-kinase) double-target inhibitor is used for selectively inhibiting tumor cell messenger core protein kinase target PI3K and epigenetic target HDAC which are synergized, and is capable of destroying the network of tumor cell messengers, thus exerting a great killing effect on various tumor cells. In multiple blood and entity heterogenic transplanted tumor animal models, the inhibitor can be used for intensively effectively inhibiting tumor growth and especially has a remarkable effect on various blood B-cell malignant tumors, and safety evaluation tests indicate that the inhibitor has high safety and security. The pyrantel compound and preparation can be used for effectively treating patients with later reoccurrence of lymphoma, myeloma and lymphatic leukemia or drug resistance.
- -
-
Paragraph 0123; 0124; 0125
(2017/08/22)
-
- Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignancies
-
Combinations of PI3K inhibitor compounds having Formula I and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hematopoietic malignancies. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed
- -
-
Page/Page column 70; 71
(2016/08/03)
-
- Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
-
The invention provides a compound of Formula I, Pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment of phosphoinositide 3-kinase related diseases and disorders such as cancer. The instant application further relates to the treatment of histone deacetylase related disorders and diseases related to both histone deacetylase and phosphoinositide 3-kinase.
- -
-
Page/Page column 37
(2016/02/26)
-
- The structure containing [...] of thienopyrimidines preparation and application
-
The invention discloses a thienopyrimidine compound containing a chromone hydrazone structure, a geometrical isomer of the compound, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compound, as well as application of the compound to preparation of medicines for treating and/or preventing hyperplastic diseases, application of the compound to preparation of medicines for treating and/or preventing cancers and application of the compound to preparation of medicines for treating and/or preventing lung cancers, liver cancers, gastric cancers, colon cancers and breast cancers.
- -
-
Paragraph 0117; 0122; 0123
(2016/11/21)
-
- PHOSPHOINOSITIDE 3-KINASE INHIBITORS WITH ZINC BINDING MOIETY
-
PROBLEM TO BE SOLVED: To provide phosphoinositide 3-kinase inhibitors with a zinc binding moiety. SOLUTION: There is provided a compound represented by formula (I) in the figure. (X is S, O or the like; Y is CH, N or the like; G1 is optionally substituted N or the like; R1 and R2 are each independently H or the like; C is a substituted heterocycle or the like; B is a linear alkyl or the like; Ra and Rb together with the nitrogen atom coupled to them are morpholino or the like; G2 is an indazole ring or the like; q, r and s are independently from 0 to 1, provided that at least one of them is 1; t is from 0 to 1; n is from 0 to 4; and p is from 0 to 2.) COPYRIGHT: (C)2016,JPOandINPIT
- -
-
Paragraph 0174
(2016/10/07)
-
- Phosphoinositides 3-serinekinase inhibitor compd. antialopecic agent and combinations, and method of use
-
Combinations of PI3K inhibitor compounds having Formulas I and II and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hyperproliferative disorders such as cancer. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
- -
-
Paragraph 0334-0335
(2016/10/09)
-
- Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors
-
Two series of thienopyrimidine derivatives (10a-k, 16a-j) bearing chromone moiety were designed and synthesized. All the compounds were evaluated for inhibitory activity against mTOR kinase at a concentration of 10uM. Four selected compounds were further evaluated for the IC50 values against mTOR kinase, PI3Kα kinase and two cancer cell lines. Some of the target compounds exhibited moderate to excellent mTOR/PI3Kα kinase inhibitory activity and cytotoxicity. The most promising compound 16i showed good inhibitory activity against mTOR/PI3Kα kinase and good antitumor potency for H460 and PC-3 cell lines with IC50 values of 0.16 ± 0.03 μM, 2.35 ± 0.19 μM, 1.20 ± 0.23 μM and 0.85 ± 0.04 μM, which were 8.6, >5, 7.9 and 19.1 times more active than compound I (1.37 ± 0.07 μM, >10 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), respectively. Structure-activity relationships (SARs) and docking studies indicated that the chromone moiety is necessary for the potent antitumor activity and cytotoxicity of these compounds. Substitution of the chromone moiety at the 6-position has a significant impact to the inhibitory activity, in particular a carboxylic acid group, produced the best potency.
- Zhu, Wufu,Chen, Chen,Sun, Chengyu,Xu, Shan,Wu, Chunjiang,Lei, Fei,Xia, Hui,Tu, Qidong,Zheng, Pengwu
-
-
- Synthesis and anticancer activities of thieno[3,2-d]pyrimidines as novel HDAC inhibitors
-
A series of thieno[3,2-d]pyrimidines bearing a hydroxamic acid moiety as novel HDAC inhibitors were designed and synthesized. The structures of the new synthesized compounds were confirmed using IR, 1H, 13C NMR spectrum. Compounds 11-13 showed potent inhibitory activities against HDACs with IC50 values at 0.38, 0.49 and 0.61 μM. Most of target compounds displayed strong anti-proliferative activity by a MTT assay on three human cancer cell lines including HCT-116, MCF-7 and HeLa. Compound 11, having potent inhibitory activities against HDACs, induced apoptosis and G2/M cell cycle arrest in HCT-116 cell line.
- Tan, Qiu,Zhang, Zhitao,Hui, Jie,Zhao, Yu,Zhu, Li
-
p. 358 - 365
(2014/01/17)
-
- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
-
The present invention provides a method of treating a cancer associated with a K-ras mutation in a subject in need thereof. The method comprises the steps of: (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) administering to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
- -
-
Paragraph 0176
(2013/05/08)
-
- A practical synthesis of a PI3K inhibitor under noncryogenic conditions via functionalization of a lithium triarylmagnesiate intermediate
-
We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions to produce the corresponding aldehyde. We also investigated aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling. Final deprotection and salt formation afforded the API.
- Tian, Qingping,Cheng, Zhigang,Yajima, Herbert M.,Savage, Scott J.,Green, Keena L.,Humphries, Theresa,Reynolds, Mark E.,Babu, Srinivasan,Gosselin, Francis,Askin, David,Kurimoto, Isao,Hirata, Norihiko,Iwasaki, Mitsuhiro,Shimasaki, Yasuharu,Miki, Takashi
-
-
- Design, synthesis and anticancer activity of 4-morpholinothieno[3,2-d]- pyrimidine derivatives bearing arylmethylene hydrazine moiety
-
Three series of 4-morpholinothieno[3,2-d]pyrimidine derivatives containing arylmethylene hydrazine moiety (11a-f, 13a-k and 15a-h) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. The synthesized compounds were evaluated for their cytotoxicity against three cancer cell lines (H460, HT-29, MDA-MB-231). Most of them exhibited moderate to significant cytotoxicity and high-selectivity against one or more cell lines, especially compounds 11c, 13b, 15f and 15g possessing dramatically increased cytotoxicity as compared with the positive controls, which were further evaluated for six other cancer cell lines and one normal cell line. The most promising compound 11c, bearing 3,4-methylenedioxy phenyl group, showed remarkable cytotoxicity against H460, HT-29 and MDA-MB-231 cell lines with IC50 values of 0.003 μM, 0.42 μM and 0.74 μM, which was 1.6- to 290-fold more potent than GDC-0941.
- Zhu, Wufu,Zhai, Xin,Fu, Qiangqiang,Guo, Fei,Bai, Mei,Wang, Jianqiang,Wang, Haiyan,Gong, Ping
-
experimental part
p. 1037 - 1045
(2012/10/08)
-
- Design, synthesis and 3D-QSAR analysis of novel 2-hydrazinyl-4- morpholinothieno[3,2-d]pyrimidine derivatives as potential antitumor agents
-
A series of 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and evaluated for their cytotoxic activities against five cancer cell lines. Most of them exhibited moderate to significant cytotoxic activities and high-selectivity against one or more cell lines, and nearly all of them had higher potency than positive controls against MDA-MB-231 cell line. The most promising compound 15f showed strong cytotoxic activities against H460, HT-29 and MDA-MB-231 cell lines, which were 1.7- to 66.5-folds more active than 2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)-1-piperazinyl)methyl)-4-(4- morpholinyl)thieno[3,2-d]pyrimidine(GDC-0941). To investigate the SARs of thieno[3,2-d]pyrimidine derivatives in more details, CoMFA (q2 = 0.436, r2 = 0.937) and CoMSIA (q2 = 0.706, r2 = 0.947) models on H460 cell line were established. The generated 3D-QSAR models can be used for further rational design of novel thienopyrimidines as highly potent and selective cytotoxic agents.
- Zhu, Wufu,Liu, Yajing,Zhai, Xin,Wang, Xiao,Zhu, Yan,Wu, Di,Zhou, Hongyu,Gong, Ping,Zhao, Yanfang
-
p. 162 - 175
(2013/01/15)
-
- Synthesis and cytotoxic activity of novel 2,6-disubstituted-4-mor- pholinothieno[3,2-d]pyrimidines as potent anti-tumor agents
-
A series of 2,6-disubstituted-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and their cytotoxic activity against H460, HT-29, MDA-MB-231, U87MG and H1975 cancer cell lines were evaluated in vitro. Most of the target compounds exhibited moderate to excellent activity to the tested cell lines. The most promising compound 23 (0.84 μmol/L, 0.23 μmol/L, 2.52 μmol/L, 1.80 μmol/L) was 1.0, 2.9, 29.3 and 4.3 times more active than GDC-0941 (0.87 μmol/L, 0.66 μmol/L, 73.8 μmol/L, 7.77 μmol/L) against H460, HT-29, MDA-MB-231 and U87MG cell lines, respectively.
- Zhu, Wu Fu,Zhai, Xin,Li, Sai,Cao, Yun Yun,Gong, Ping,Liu, Ya Jing
-
scheme or table
p. 703 - 706
(2012/07/16)
-
- Potent and highly selective benzimidazole inhibitors of PI3-kinase delta
-
Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3Kδ. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.
- Murray, Jeremy M.,Sweeney, Zachary K.,Chan, Bryan K.,Balazs, Mercedesz,Bradley, Erin,Castanedo, Georgette,Chabot, Christine,Chantry, David,Flagella, Michael,Goldstein, David M.,Kondru, Rama,Lesnick, John,Li, Jun,Lucas, Matthew C.,Nonomiya, Jim,Pang, Jodie,Price, Stephen,Salphati, Laurent,Safina, Brian,Savy, Pascal P. A.,Seward, Eileen M.,Ultsch, Mark,Sutherlin, Daniel P.
-
p. 7686 - 7695
(2012/10/29)
-
- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
-
The present invention provides a method of treating a cancer associated with a K- ras mutation in a subject in need thereof. The method comprises the steps of (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) adminsiterign to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Page/Page column 129
(2011/11/01)
-
- PI3 KINASE INHIBITORS AND USES THEREOF
-
The present invention provides compounds, compositions thereof, and methods of using the same.
- -
-
Page/Page column 247
(2011/10/10)
-
- LIGAND-DIRECTED COVALENT MODIFICATION OF PROTEIN
-
The present invention relates to enzyme inhibitors. More specifically, the present invention relates to ligand-directed covalent modification of proteins; method of designing same; pharmaceutical formulation of same; and method of use.
- -
-
Page/Page column
(2013/03/26)
-
- COMBINATIONS OF PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND CHEMOTHERAPEUTIC AGENTS FOR THE TREATMENT OF HEMATOPOIETIC MALIGNANCIES
-
Combinations of PI3K inhibitor compounds having Formula I and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hematopoietic malignancies. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
- -
-
-
- Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor
-
Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor.
- Heffron, Timothy P.,Berry, Megan,Castanedo, Georgette,Chang, Christine,Chuckowree, Irina,Dotson, Jennafer,Folkes, Adrian,Gunzner, Janet,Lesnick, John D.,Lewis, Cristina,Mathieu, Simon,Nonomiya, Jim,Olivero, Alan,Pang, Jodie,Peterson, David,Salphati, Laurent,Sampath, Deepak,Sideris, Steve,Sutherlin, Daniel P.,Tsui, Vickie,Wan, Nan Chi,Wang, Shumei,Wong, Susan,Zhu, Bing-yan
-
scheme or table
p. 2408 - 2411
(2010/07/16)
-
- THIENOPYRIMIDIENE DERIVATIVES AS PI3K INHIBITORS
-
Thienopyrimidines of formula (I) wherein W and R1 to R4 are as defined in the claims, and the pharmaceutically acceptable salts thereof are inhibitors of PI3K and are selective for the p110δ isoform, which is a class Ia PI3 kinase, over both other class Ia and class Ib kinases. The compounds may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.
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-
Page/Page column 64
(2009/05/28)
-
- Pharmaceutical compounds
-
A thienopyrimidine of formula (I): and the pharmaceutically acceptable salts thereof have activity as inhibitors of PI3K with selectivity for the P110α subtype, and may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour, particularly those associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Processes for synthesizing the compounds are also described.
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-
Page/Page column 7
(2008/06/13)
-
- Pharmaceutical compounds
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Compounds of Formulae Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia and Ib for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 73
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- PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND METHODS OF USE
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Compounds of Formulas Ia-d where X is S or O, mor is a morpholine group, and R3 is a monocyclic heteroaryl group, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for modulating the activity of lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia-d for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. [Insert Formula Ic and Id]
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Page/Page column 133
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- PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND METHODS OF USE
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Compounds of Formulas Ia-d where X is S or O, mor is a morpholine group, and R3 is a monocyclic heteroaryl group, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for modulating the activity of lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia-d for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. Formula (Ic) and (Id).
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Page/Page column 160
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- PYRIMIDINE DERIVATIVES AS PI3K INHIBITORS
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Thienopyrimidines of formula (Ia) or (Ib): wherein R1, R2, R3, are as defined in the claims.
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Page/Page column 62-63
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- PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds of Formulas (Ia) and (Ib), and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula (Ia) and (Ib) for in vitro, in situ, and in vivodiagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 135-136
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- PHARMACEUTICAL COMPOUNDS
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Fused pyrimidines of formula (I); wherein A represents a thiophene or furan ring; n is 1 or 2; R1 is a group of formula (II); wherein m is 0 or 1; R30 is H or C1-C6 alkyl; R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and O, which may be fused to a benzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N-containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated N-containing heterocyclic group as defined above; R2 is selected from formula (a); wherein R6 and R7 form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepane or thiazepane group which is unsubstituted or substituted; and formula (b); wherein Y is a C2-C4 alkylene chain which contains, between constituent carbon atoms of the chain and/or at one or both ends of the chain, 1 or 2 heteroatoms selected from O, N and S, and which is unsubstituted or substituted; and R3 is an indazole group which is unsubstituted or substituted; and the pharmaceutically acceptable salt thereof have activity as inhibitors of P13K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with P13 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Processes for synthesizing the compounds are also described.
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Page/Page column 29-30
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