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Journal of medicinal chemistry
Oct 10, 2024;67 (19): 17429-17453.

Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T-Cell Immunity against Cancer.

Jeffrey Mowat, Rafael Carretero, Gabriele Leder, Nuria Aiguabella Font, Roland Neuhaus, Sandra Berndt, Judith G��nther, Anders Friberg, Martina Sch��fer, Hans Briem, Marian Raschke, Hideki Miyatake Ondozabal, Bernd Buchmann, Ulf Boemer, Bertolt Kreft, Ingo V Hartung, Rienk Offringa
Author Information
  1. Jeffrey Mowat: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  2. Rafael Carretero: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  3. Gabriele Leder: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  4. Nuria Aiguabella Font: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  5. Roland Neuhaus: DKFZ-Bayer Joint Immunotherapeutics Laboratory, German Cancer Research Center, Heidelberg 69120, Germany.
  6. Sandra Berndt: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  7. Judith G��nther: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany. ORCID
  8. Anders Friberg: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany. ORCID
  9. Martina Sch��fer: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  10. Hans Briem: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany. ORCID
  11. Marian Raschke: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  12. Hideki Miyatake Ondozabal: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany. ORCID
  13. Bernd Buchmann: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  14. Ulf Boemer: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  15. Bertolt Kreft: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  16. Ingo V Hartung: Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
  17. Rienk Offringa: DKFZ-Bayer Joint Immunotherapeutics Laboratory, German Cancer Research Center, Heidelberg 69120, Germany. ORCID
PMID: 39331123 DOI: 10.1021/acs.jmedchem.4c01325

Abstract

Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) is a serine/threonine kinase that acts as an immune checkpoint downstream of T-cell receptor stimulation. MAP4K1 activity is enhanced by prostaglandin E2 (PGE2) and transforming growth factor beta (TGF��), immune modulators commonly present in the tumor microenvironment. Therefore, its pharmacological inhibition is an attractive immuno-oncology concept for inducing therapeutic T-cell responses in cancer patients. Here, we describe the systematic optimization of azaindole-based lead compound , resulting in the discovery of potent and selective MAP4K1 inhibitor (BAY-405) that displays nanomolar potency in biochemical and cellular assays as well as in vivo exposure after oral dosing. BAY-405 enhances T-cell immunity and overcomes the suppressive effect of PGE2 and TGF��. Treatment of tumor-bearing mice shows T-cell-dependent antitumor efficacy. MAP4K1 inhibition in conjunction with PD-L1 blockade results in a superior antitumor impact, illustrating the complementarity of the single agent treatments.

References

  1. J Med Chem. 2018 Jul 12;61(13):5525-5546 [PMID: 29775538]
  2. Genes Dev. 1996 Sep 15;10(18):2251-64 [PMID: 8824585]
  3. J Biol Chem. 2001 Nov 30;276(48):45207-16 [PMID: 11487585]
  4. J Cell Biochem. 2005 May 1;95(1):34-44 [PMID: 15770651]
  5. Drug Discov Today. 2013 Aug;18(15-16):724-31 [PMID: 23557664]
  6. Adv Immunol. 2016;129:277-314 [PMID: 26791862]
  7. J Chem Inf Model. 2020 Jun 22;60(6):2903-2914 [PMID: 32369360]
  8. ChemMedChem. 2008 Dec;3(12):1893-904 [PMID: 18973168]
  9. Cancer Immunol Immunother. 2010 Mar;59(3):419-29 [PMID: 19787351]
  10. Expert Opin Ther Pat. 2021 Oct;31(10):893-910 [PMID: 33956554]
  11. Physiol Rev. 2011 Jul;91(3):973-1007 [PMID: 21742793]
  12. Science. 2017 Dec 1;358(6367): [PMID: 29191878]
  13. J Exp Med. 2007 Mar 19;204(3):681-91 [PMID: 17353368]
  14. Heliyon. 2023 Mar 09;9(3):e14238 [PMID: 36950615]
  15. Drug Discov Today. 2020 Sep;25(9):1702-1709 [PMID: 32652309]
  16. Cancer Discov. 2018 Sep;8(9):1069-1086 [PMID: 30115704]
  17. Eur J Med Chem. 2022 Dec 15;244:114819 [PMID: 36209628]
  18. J Am Chem Soc. 2018 Jun 27;140(25):8037-8047 [PMID: 29916711]
  19. Blood. 2009 Jul 16;114(3):535-46 [PMID: 19451549]
  20. J Med Chem. 2014 Mar 27;57(6):2704-13 [PMID: 24601597]
  21. J Cell Biol. 2011 Nov 28;195(5):839-53 [PMID: 22105350]
  22. Small GTPases. 2014;5:e29846 [PMID: 25010901]
  23. Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501 [PMID: 20383002]
  24. J Biol Chem. 2001 Jun 1;276(22):18908-14 [PMID: 11279207]
  25. Nat Immunol. 2007 Jan;8(1):84-91 [PMID: 17115060]
  26. J Immunol Methods. 2014 Mar;405:192-8 [PMID: 24486140]
  27. Methods Enzymol. 2003;374:300-21 [PMID: 14696379]
  28. J Med Chem. 2022 Jun 23;65(12):8065-8090 [PMID: 35696642]
  29. Annu Rev Immunol. 1997;15:371-404 [PMID: 9143693]
  30. Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32 [PMID: 20124692]
  31. Cell Rep. 2018 Oct 2;25(1):80-94 [PMID: 30282040]
  32. Nat Rev Drug Discov. 2022 Nov;21(11):821-840 [PMID: 35982333]
  33. J Org Chem. 2006 Jul 21;71(15):5538-45 [PMID: 16839132]
  34. J Am Chem Soc. 2016 Jul 6;138(26):8084-7 [PMID: 27263662]
  35. Elife. 2023 Apr 19;12: [PMID: 37073955]
  36. BMC Bioinformatics. 2017 Jan 5;18(1):17 [PMID: 28056771]
  37. J Med Chem. 2004 Mar 25;47(7):1750-9 [PMID: 15027866]
  38. Nat Rev Dis Primers. 2020 May 7;6(1):38 [PMID: 32382051]
  39. Ann Oncol. 2017 Jul 1;28(suppl_4):iv119-iv142 [PMID: 28881921]
  40. Immunol Res. 2012 Dec;54(1-3):262-5 [PMID: 22477524]

MeSH Term

Animals
Humans
T-Lymphocytes
Mice
Protein Kinase Inhibitors
Antineoplastic Agents
Protein Serine-Threonine Kinases
Indoles
Cell Line, Tumor
Drug Discovery
Aza Compounds
Female
Structure-Activity Relationship
Neoplasms
Mice, Inbred C57BL

Chemicals

Protein Kinase Inhibitors
Antineoplastic Agents
Protein Serine-Threonine Kinases
Indoles
Aza Compounds
Journal Article
Article has an altmetric score of 5

Word Cloud

Created with Highcharts 10.0.0kinaseMAP4K1T-cellimmunePGE2TGF��inhibitionBAY-405antitumorMitogen-activatedprotein1serine/threonineactscheckpointdownstreamreceptorstimulationactivityenhancedprostaglandinE2transforminggrowthfactorbetamodulatorscommonlypresenttumormicroenvironmentThereforepharmacologicalattractiveimmuno-oncologyconceptinducingtherapeuticresponsescancerpatientsdescribesystematicoptimizationazaindole-basedleadcompoundresultingdiscoverypotentselectiveinhibitordisplaysnanomolarpotencybiochemicalcellularassayswellvivoexposureoraldosingenhancesimmunityovercomessuppressiveeffectTreatmenttumor-bearingmiceshowsT-cell-dependentefficacyconjunctionPD-L1blockaderesultssuperiorimpactillustratingcomplementaritysingleagenttreatmentsDiscoveryBAY-405:Azaindole-BasedInhibitorEnhancementT-CellImmunityCancer

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