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Potent and selective inhibitors of PI3Kδ: obtaining isoform selectivity from the affinity pocket and tryptophan shelf.

Sutherlin DP, Baker S, Bisconte A, Blaney PM, Brown A, Chan BK, Chantry D, Castanedo G, DePledge P, Goldsmith P, Goldstein DM, Hancox T, Kaur J, Knowles D, Kondru R, Lesnick J, Lucas MC, Lewis C, Murray J, Nadin AJ, Nonomiya J, Pang J, Pegg N, Price S, Reif K, Safina BS, Salphati L, Staben S, Seward EM, Shuttleworth S, Sohal S, Sweeney ZK, Ultsch M, Waszkowycz B, Wei B
Bioorg Med Chem Lett 22 4296-302 (2012)
Related entries: 4ezk, 4ezl

Cited: 21 times
EuropePMC logo PMID: 22672799

Abstract

A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.

Reviews - 4ezj mentioned but not cited (2)

  1. Structural Determinants of Isoform Selectivity in PI3K Inhibitors. Miller MS, Thompson PE, Gabelli SB. Biomolecules 9 E82 (2019)
  2. Advances in chemical proteomic evaluation of lipid kinases-DAG kinases as a case study. Ware TB, Hsu KL. Curr Opin Chem Biol 65 101-108 (2021)

Articles - 4ezj mentioned but not cited (1)

  1. Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors. Ferguson FM, Ni J, Zhang T, Tesar B, Sim T, Kim ND, Deng X, Brown JR, Zhao JJ, Gray NS. ACS Med Chem Lett 7 908-912 (2016)


Reviews citing this publication (3)

  1. PI3K inhibitors are finally coming of age. Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. Nat Rev Drug Discov 20 741-769 (2021)
  2. Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors. Welker ME, Kulik G. Bioorg Med Chem 21 4063-4091 (2013)
  3. Targeting PI3Kδ: emerging therapy for chronic lymphocytic leukemia and beyond. Wei M, Wang X, Song Z, Jiao M, Ding J, Meng LH, Zhang A. Med Res Rev 35 720-752 (2015)

Articles citing this publication (15)

  1. Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization. Han K, Xu X, Chen G, Zeng Y, Zhu J, Du X, Zhang Z, Cao B, Liu Z, Mao X. J Hematol Oncol 7 9 (2014)
  2. Identification of GNE-293, a potent and selective PI3Kδ inhibitor: navigating in vitro genotoxicity while improving potency and selectivity. Safina BS, Sweeney ZK, Li J, Chan BK, Bisconte A, Carrera D, Castanedo G, Flagella M, Heald R, Lewis C, Murray JM, Nonomiya J, Pang J, Price S, Reif K, Salphati L, Seward EM, Wei B, Sutherlin DP. Bioorg Med Chem Lett 23 4953-4959 (2013)
  3. Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase β isoform. Staben ST, Ndubaku C, Blaquiere N, Belvin M, Bull RJ, Dudley D, Edgar K, Gray D, Heald R, Heffron TP, Jones GE, Jones M, Kolesnikov A, Lee L, Lesnick J, Lewis C, Murray J, McLean NJ, Nonomiya J, Olivero AG, Ord R, Pang J, Price S, Prior WW, Rouge L, Salphati L, Sampath D, Wallin J, Wang L, Wei B, Weismann C, Wu P. Bioorg Med Chem Lett 23 2606-2613 (2013)
  4. From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome. Henley ZA, Bax BD, Inglesby LM, Champigny A, Gaines S, Faulder P, Le J, Thomas DA, Washio Y, Baldwin IR. ACS Med Chem Lett 8 1093-1098 (2017)
  5. Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles. Safina BS, Elliott RL, Forrest AK, Heald RA, Murray JM, Nonomiya J, Pang J, Salphati L, Seward EM, Staben ST, Ultsch M, Wei B, Yang W, Sutherlin DP. ACS Med Chem Lett 8 936-940 (2017)
  6. Discovery of triazole aminopyrazines as a highly potent and selective series of PI3Kδ inhibitors. Terstiege I, Perry M, Petersen J, Tyrchan C, Svensson T, Lindmark H, Öster L. Bioorg Med Chem Lett 27 679-687 (2017)
  7. Design, Synthesis, and Development of Pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part II-Benzimidazole Derivatives. Stypik M, Michałek S, Orłowska N, Zagozda M, Dziachan M, Banach M, Turowski P, Gunerka P, Zdżalik-Bielecka D, Stańczak A, Kędzierska U, Mulewski K, Smuga D, Maruszak W, Gurba-Bryśkiewicz L, Leniak A, Pietruś W, Ochal Z, Mach M, Zygmunt B, Pieczykolan J, Dubiel K, Wieczorek M. Pharmaceuticals (Basel) 15 927 (2022)
  8. Design, Synthesis, and Development of pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part I-Indole Derivatives. Stypik M, Zagozda M, Michałek S, Dymek B, Zdżalik-Bielecka D, Dziachan M, Orłowska N, Gunerka P, Turowski P, Hucz-Kalitowska J, Stańczak A, Stańczak P, Mulewski K, Smuga D, Stefaniak F, Gurba-Bryśkiewicz L, Leniak A, Ochal Z, Mach M, Dzwonek K, Lamparska-Przybysz M, Dubiel K, Wieczorek M. Pharmaceuticals (Basel) 15 949 (2022)
  9. Development of single and mixed isoform selectivity PI3Kδ inhibitors by targeting Asn836 of PI3Kδ. Miller MS, Mountford SJ, Pinson JA, Zheng Z, Künzli M, Patel V, Hogg SJ, Shortt J, Jennings IG, Thompson PE. Bioorg Med Chem Lett 26 4790-4794 (2016)
  10. Identification of new dual spleen tyrosine kinase (Syk) and phosphoionositide-3-kinase δ (PI3Kδ) inhibitors using ligand and structure-based integrated ideal pharmacophore models. Kaur M, Silakari O. SAR QSAR Environ Res 27 469-499 (2016)
  11. Molecular dynamics and integrated pharmacophore-based identification of dual [Formula: see text] inhibitors. Kaur M, Singh PK, Singh M, Bahadur R, Silakari O. Mol Divers 22 95-112 (2018)
  12. Optimization of Versatile Oxindoles as Selective PI3Kδ Inhibitors. Methot JL, Achab A, Christopher M, Zhou H, McGowan MA, Trotter BW, Fradera X, Lesburg CA, Goldenblatt P, Hill A, Chen D, Otte KM, Augustin M, Shah S, Katz JD. ACS Med Chem Lett 11 2461-2469 (2020)
  13. Synthesis and PI 3-Kinase Inhibition Activity of Some Novel 2,4,6-Trisubstituted 1,3,5-Triazines. Nelson RA, Schronce T, Huang Y, Albugami A, Kulik G, Welker ME. Molecules 23 E1628 (2018)
  14. Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors. Buron F, Rodrigues N, Saurat T, Hiebel MA, Bourg S, Bonnet P, Nehmé R, Morin P, Percina N, Corret J, Vallée B, le Guevel R, Jourdan ML, Bénédetti H, Routier S. Molecules 26 5349 (2021)
  15. Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines. Wright EW, Nelson RA, Karpova Y, Kulik G, Welker ME. Molecules 23 E1675 (2018)


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