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Future Medicinal Chemistry Volume 10, 2018 - Issue 20
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Research Article

Discovery of 2-(aminopyrimidin-5-yl)-4-(morpholin-4-yl)-6- Substituted Triazine as PI3K and BRAF Dual Inhibitor

Hui-Yan Wang1 Department of Medicinal ChemistrySchool of PharmacyXi′an Jiaotong UniversityXi′anShaanxi710061PR China
,
Ying Shen1 Department of Medicinal ChemistrySchool of PharmacyXi′an Jiaotong UniversityXi′anShaanxi710061PR China
,
Hao Zhang1 Department of Medicinal ChemistrySchool of PharmacyXi′an Jiaotong UniversityXi′anShaanxi710061PR China
,
Yuan-Yuan Hei1 Department of Medicinal ChemistrySchool of PharmacyXi′an Jiaotong UniversityXi′anShaanxi710061PR China
,
Hong-Yi Zhao1 Department of Medicinal ChemistrySchool of PharmacyXi′an Jiaotong UniversityXi′anShaanxi710061PR China
,
Minhang Xin1 Department of Medicinal ChemistrySchool of PharmacyXi′an Jiaotong UniversityXi′anShaanxi710061PR China
,
She-Min Lu2 Department of Biochemistry & Molecular BiologySchool of Basic Medical ScienceXi′an Jiaotong UniversityXi′anShaanxi710061PR China
&
San-Qi Zhang1 Department of Medicinal ChemistrySchool of PharmacyXi′an Jiaotong UniversityXi′anShaanxi710061PR ChinaCorrespondence[email protected]
 show all
Pages 2445-2455 | Received 24 Apr 2018, Accepted 15 Aug 2018, Published online: 16 Oct 2018

References

  • Engelman JA Luo J Cantley LC . The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet.7 (8), 606 – 619 (2006).
  • Yap TA Garrett MD Walton MI Raynaud F de-Bono JS Workman P . Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises. Curr. Opin. Pharmacol.8 (4), 393 – 412 (2008).
  • Liu P Cheng H Roberts TM Zhao JJ . Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov.8 (8), 627 – 644 (2009).
  • Fruman DA Rommel C . PI3K and cancer: lessons, challenges and opportunities. Nat. Rev. Drug Discov.13 (2), 140 – 156 (2014).
  • Knight SD Adams ND Burgess JL et al. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS. Med. Chem. Lett.1 (1), 39 – 43 (2010).
  • Maira SM Stauffer F Brueggen J et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther.7 (7), 1851 – 1863 (2008).
  • Sutherlin DP Bao L Berry M et al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J. Med. Chem.54 (21), 7579 – 7587 (2011).
  • Hart S Novotny-Diermayr V Goh KC et al. VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Mol. Cancer Ther.12 (2), 151 – 161 (2013).
  • Burger MT Pecchi S Wagman A et al. Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer. ACS Med. Chem. Lett.2 (10), 774 – 779 (2011).
  • Shao T Wang J Chen JG et al. Discovery of 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides as novel PI3K inhibitors and anticancer agents by bioisostere. Eur. J. Med. Chem.75 (6), 96 – 105 (2014).
  • Li H Wang XM Wang J et al. Combination of 2-methoxy-3-phenylsulfonylamino benzamide and 2-aminobenzothiazole to discover novel anticancer agents. Bioorg. Med. Chem.22 (14), 3739 – 3748 (2014).
  • Wang XM Mao S Cao L et al. Modification of N-(6-(2-methoxy-3-(4-fluorophenyl sulfonamido)pyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide as PI3Ks inhibitor by replacement of the acetamide group with alkylurea. Bioorg. Med. Chem.23 (17), 5662 – 5671 (2015).
  • Xie XX Li H Wang J et al. Synthesis and anticancer effects evaluation of 1-alkyl-3- (6-(2-methoxy-3-sulfonylaminopyridin-5-yl)benzo[d]thiazol-2-yl)urea as anticancer agents with low toxicity. Bioorg. Med. Chem.23 (19), 6477 – 6485 (2015).
  • Kolev VN Wright QG Vidal CM et al. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res.75 (2), 446 – 455 (2015).
  • Wellbrook C Karasarides M Marais R . The RAF proteins take centre stage. Nat. Rev. Mol. Cell. Biol.5 (11), 875 – 885 (2004).
  • Davies H Bignell GR Cox C et al. Mutations of the BRAF gene in human cancer. Nature417 (6892), 949 – 954 (2002).
  • Chapman PB Hauschild A Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med.364 (26), 2507 – 2516 (2011).
  • Nishiguchi GA Rico A Tanner H et al. Design and discovery of N-(2-Methyl-5′- morpholino-6′-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3′-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): a potent, selective, and efficacious RAF inhibitor targeting RAS mutant cancers. J. Med. Chem.60 (12), 4869 – 4881 (2017).
  • Vasbinder MM Aquila B Augustin M et al. Discovery and optimization of a novel series of potent mutant B-RafV600E selective kinase inhibitors. J. Med. Chem.56 (5), 1996 – 2015 (2016).
  • Lu B Cao H Cao J et al. Discovery of EBI-907: a highly potent and orally active B-RafV600E inhibitor for the treatment of melanoma and associated cancers. Bioorg. Med. Chem. Lett.26 (3), 819 – 823 (2016).
  • Millet A Martin AR Ronco C Rocchi S Benhida R . Metastatic melanoma: insights into the evolution of the treatments and future challenges. Med. Res. Rev.37 (1), 98 – 148 (2017).
  • Zhang W . BRAF inhibitors: the current and the future. Curr. Opin. Pharmacol.23, 68 – 73 (2015).
  • Asati V Mahapatra DK Bharti SK . PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: structural and pharmacological perspectives. Eur. J. Med. Chem.109, 314 – 341 (2016).
  • Aksamitiene E Kiyatkin A Kholodenko BN . Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem. Soc. Trans.40 (1), 139 – 146 (2012).
  • Chandarlapaty S . Negative feedback and adaptive resistance to the targeted therapy of cancer. Cancer Discov.2 (4), 311 – 319 (2012).
  • Renshaw J Taylor KR Bishop R et al. Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo. Clin. Cancer Res.19 (21), 5940 – 5951 (2013).
  • Hoeflich KP Merchant M Orr C et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res.72 (1), 210 – 219 (2012).
  • Liu K Rao W Parikh H et al. 3, 5-Disubstituted-thiazolidine-2,4-dione analogs as anticancer agents: design, synthesis and biological characterization. Eur. J. Med. Chem.47 (1), 125 – 137 (2012).
  • Park H Chien PN Ryu SE . Discovery of potent inhibitors of receptor protein tyrosine phosphatase sigma through the structure based virtual screening. Bioorg. Med. Chem. Lett.22 (20), 6333 – 6337 (2012).
  • Van Dort ME Hong H Wang H et al. Discovery of bifunctional oncogenic target inhibitors against allosteric mitogen-activated protein kinase (MEK1) and phosphatidylinositol 3-kinase (PI3K). J. Med. Chem.59 (6), 2512 – 2522 (2016).
  • Scott KT Roger AS Sanjeeva R et al. WO 2014169167 A1 (2014).
  • Singh PK Silakari O . Novel EGFR (T790M)-cMET dual inhibitors: putative therapeutic agents for non-small-cell lung cancer. Future Med. Chem.9 (5), 469 – 483 (2017).
  • Lineham E Spencer J Morley SJ . Dual abrogation of MNK and mTOR: a novel therapeutic approach for the treatment of aggressive cancers. Future Med. Chem.9 (13), 1539 – 1555 (2017).
  • Zhang S Wang H Zhang H et al. CN 107652270 A (2018).
  • Wang XM Xu J Xin M Lu SM Zhang SQ . Design, synthesis and antiproliferative activity evaluation of m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamides in vitro. Bioorg. Med. Chem. Lett.25 (8), 1730 – 1735 (2015).
  • Plebanek E Chevrier F Roy V et al. Straightforward synthesis of 2,4,6-trisubstituted 1,3,5-triazine compounds targeting cysteine cathepsins K and S. Eur. J. Med. Chem.121, 12 – 20 (2016).
  • Wang XM Xin MH Xu J et al. Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides in vitro and in vivo. Eur. J. Med. Chem.96, 382 – 395 (2015).
  • Zhang H Xin M Xie XX et al. Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety. Bioorg. Med. Chem.23 (24), 7765 – 7776 (2015).
  • Kashem MA Nelson RM Yingling JD et al. Three mechanistically distinct kinase assays compared: measurement of intrinsic ATPase activity identified the most comprehensive set of ITK inhibitors. J. Biomol. Screen.12 (1), 70 – 83 (2007).
  • Talele TT . The ‘cyclopropyl fragment’ is a versatile player that frequently appears in preclinical/clinical drug molecules. J. Med. Chem.59 (19), 8712 – 8756 (2016).
  • Zhang H Wang J Shen Y et al. Discovery of 2,4,6-trisubstitued pyrido[3,4-d]pyrimidine derivatives as new EGFR-TKIs. Eur. J. Med. Chem.148, 221 – 237 (2018).

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