2og8 Citations

Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity.


The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.

Articles - 2og8 mentioned but not cited (1)

  1. Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases. Xu Q, Malecka KL, Fink L, Jordan EJ, Duffy E, Kolander S, Peterson JR, Dunbrack RL. Sci Signal 8 rs13 (2015)

Reviews citing this publication (2)

  1. Update on lymphocyte specific kinase inhibitors: a patent survey. Martin MW, Machacek MR. Expert Opin Ther Pat 20 1573-1593 (2010)
  2. T-cell-targeted signaling inhibitors. Won J, Lee GH. Int. Rev. Immunol. 27 19-41 (2008)

Articles citing this publication (19)

  1. Small-molecule activators of TMEM16A, a calcium-activated chloride channel, stimulate epithelial chloride secretion and intestinal contraction. Namkung W, Yao Z, Finkbeiner WE, Verkman AS. FASEB J. 25 4048-4062 (2011)
  2. Small molecule recognition of c-Src via the Imatinib-binding conformation. Dar AC, Lopez MS, Shokat KM. Chem. Biol. 15 1015-1022 (2008)
  3. Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases. Link W, Oyarzabal J, Serelde BG, Albarran MI, Rabal O, Cebriá A, Alfonso P, Fominaya J, Renner O, Peregrina S, Soilán D, Ceballos PA, Hernández AI, Lorenzo M, Pevarello P, Granda TG, Kurz G, Carnero A, Bischoff JR. J. Biol. Chem. 284 28392-28400 (2009)
  4. Kinase inhibitors for the treatment of inflammatory and autoimmune disorders. Bhagwat SS. Purinergic Signal. 5 107-115 (2009)
  5. Sequence determinants of a specific inactive protein kinase conformation. Hari SB, Merritt EA, Maly DJ. Chem. Biol. 20 806-815 (2013)
  6. Discovery of 4-amino-5,6-biaryl-furo[2,3-d]pyrimidines as inhibitors of Lck: development of an expedient and divergent synthetic route and preliminary SAR. DiMauro EF, Newcomb J, Nunes JJ, Bemis JE, Boucher C, Buchanan JL, Buckner WH, Cheng A, Faust T, Hsieh F, Huang X, Lee JH, Marshall TL, Martin MW, McGowan DC, Schneider S, Turci SM, White RD, Zhu X. Bioorg. Med. Chem. Lett. 17 2305-2309 (2007)
  7. Affinity reagents that target a specific inactive form of protein kinases. Ranjitkar P, Brock AM, Maly DJ. Chem. Biol. 17 195-206 (2010)
  8. Affinity-based probes based on type II kinase inhibitors. Ranjitkar P, Perera BG, Swaney DL, Hari SB, Larson ET, Krishnamurty R, Merritt EA, Villén J, Maly DJ. J. Am. Chem. Soc. 134 19017-19025 (2012)
  9. Small-molecule inhibitors binding to protein kinase. Part II: the novel pharmacophore approach of type II and type III inhibition. Backes A, Zech B, Felber B, Klebl B, Müller G. Expert Opin Drug Discov 3 1427-1449 (2008)
  10. Biphenyl derivatives incorporating urea unit as novel VEGFR-2 inhibitors: design, synthesis and biological evaluation. Wang C, Gao H, Dong J, Zhang Y, Su P, Shi Y, Zhang J. Bioorg. Med. Chem. 22 277-284 (2014)
  11. Discovery of novel 2,3-diarylfuro[2,3-b]pyridin-4-amines as potent and selective inhibitors of Lck: synthesis, SAR, and pharmacokinetic properties. Martin MW, Newcomb J, Nunes JJ, Bemis JE, McGowan DC, White RD, Buchanan JL, DiMauro EF, Boucher C, Faust T, Hsieh F, Huang X, Lee JH, Schneider S, Turci SM, Zhu X. Bioorg. Med. Chem. Lett. 17 2299-2304 (2007)
  12. Conformation-selective inhibitors reveal differences in the activation and phosphate-binding loops of the tyrosine kinases Abl and Src. Hari SB, Perera BG, Ranjitkar P, Seeliger MA, Maly DJ. ACS Chem. Biol. 8 2734-2743 (2013)
  13. Targeting the unactivated conformations of protein kinases for small molecule drug discovery. Alton GR, Lunney EA. Expert Opin Drug Discov 3 595-605 (2008)
  14. A hexylchloride-based catch-and-release system for chemical proteomic applications. Brigham JL, Perera BG, Maly DJ. ACS Chem. Biol. 8 691-699 (2013)
  15. Strong nonadditivity as a key structure-activity relationship feature: distinguishing structural changes from assay artifacts. Kramer C, Fuchs JE, Liedl KR. J Chem Inf Model 55 483-494 (2015)
  16. N-(3-(phenylcarbamoyl)arylpyrimidine)-5-carboxamides as potent and selective inhibitors of Lck: structure, synthesis and SAR. Deak HL, Newcomb JR, Nunes JJ, Boucher C, Cheng AC, DiMauro EF, Epstein LF, Gallant P, Hodous BL, Huang X, Lee JH, Patel VF, Schneider S, Turci SM, Zhu X. Bioorg. Med. Chem. Lett. 18 1172-1176 (2008)
  17. QM/QM docking method based on the variational finite localized molecular orbital approximation. Anisimov VM, Bugaenko VL. J Comput Chem 30 784-798 (2009)
  18. Exploring conformational search protocols for ligand-based virtual screening and 3-D QSAR modeling. Cappel D, Dixon SL, Sherman W, Duan J. J. Comput. Aided Mol. Des. 29 165-182 (2015)
  19. The chemistry and pharmacology of privileged pyrroloquinazolines. Chao B, Li BX, Xiao X. Medchemcomm 6 510-520 (2015)