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      Synthesis and Biological Evaluation of Novel 4-Morpholino-7,8-dihydro-5 H-thiopyrano[4,3- d]pyrimidine Derivatives Bearing Phenylpyridine/ Phenylpyrimidine-Carboxamides


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          Four series of novel 4-morpholino-7,8-dihydro-5 H-thiopyrano[4,3- d]pyrimidine derivatives 11aj, 12aj, 13ag and 14ag bearing phenylpyridine/phenylpyrimidine- carboxamide scaffolds were designed, synthesized and their IC 50 values against three cancer cell lines (A549, PC-3 and MCF-7) were evaluated. Eleven of the compounds showed moderate cytotoxicity activity against the cancer cell lines. Structure-activity relationships (SARs) and pharmacological results indicated that the introduction of phenylpyridine-carboxamide scaffold was beneficial for the activity. What’s more, the oxidation of the sulfur atom in thiopyran and various types of substituents on the aryl group have different impacts on different series of compounds. Furthermore, the positions of aryl group substituents have a slight impact on the activity of the phenylpyridine-carboxamide series compounds.

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          PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations.

          Mutations of the PIK3CA gene may predict response to phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors. Concomitant mutations in the mitogen-activated protein kinase (MAPK) pathway may mediate resistance. Tumors from patients with breast, cervical, endometrial, and ovarian cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Of 140 patients analyzed, 25 (18%) had PIK3CA mutations, including five of 14 patients with squamous cell cervical, seven of 29 patients with endometrial, six of 29 patients with breast, and seven of 60 patients with ovarian cancers. Of the 25 patients with PIK3CA mutations, 23 (median of two prior therapies) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Two (9%) of 23 patients had stable disease for more than 6 months, and seven patients (30%) had a partial response. In comparison, only seven (10%) of 70 patients with the same disease types but with wild-type PIK3CA treated on the same protocols responded (P = .04). Seven patients (30%) with PIK3CA mutations had coexisting MAPK pathway (KRAS, NRAS, BRAF) mutations (ovarian cancer, n = 5; endometrial cancer, n = 2), and two of these patients (ovarian cancer) achieved a response. PIK3CA mutations were detected in 18% of tested patients. Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors demonstrated a higher response rate than patients without mutations. A subset of patients with ovarian cancer with simultaneous PIK3CA and MAPK mutations responded to PI3K/AKT/mTOR inhibitors, suggesting that not all patients demonstrate resistance when the MAPK pathway is concomitantly activated.
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            Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises.

            The strategy of 'drugging the cancer kinome' has led to the successful development and regulatory approval of several novel molecular targeted agents. The spotlight is now shifting to the phosphatidylinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway as a key potential target. This review details the role of the pathway in oncogenesis and the rationale for inhibiting its vital components. The focus will be on the progress made in the development of novel therapies for cancer treatment, with emphasis placed on agents that have entered clinical development. Strategies involving horizontal and vertical blockade of the pathway, as well as the use of biomarkers to select appropriate patients and to provide proof of target modulation will also be highlighted. Finally, we discuss the issues and limitations involved with targeting the PI3K-AKT-mTOR pathway, and predict what the future may hold for these novel anticancer therapeutics.
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              Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design.

              The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors.

                Author and article information

                Role: Academic Editor
                31 October 2016
                November 2016
                : 21
                : 11
                : 1447
                [1 ]School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China; szliuhm@ 123456sit.edu.cn
                [2 ]School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China; wenhui410@ 123456126.com (W.W.); sunchengyu0902@ 123456126.com (C.S.); wangcllw@ 123456126.com (C.W.)
                [3 ]Pharmacy Department, The Affiliated Hospital of Chongqing Three Gorges Medical College, Chongqing 404000, China
                Author notes
                [* ]Correspondence: zhuwf@ 123456jxstnu.edu.cn (W.Z.); Zhengpw@ 123456126.com (P.Z.); Tel./Fax: +86-791-8380-2393 (P.Z.)
                © 2016 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 27 September 2016
                : 26 October 2016

                thiopyrano[4,3-d]pyrimidine,phenylpyridine/phenylpyrimidine carboxamides,synthesis,cytotoxicity activity,pi3kα kinase


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