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Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma.

Scott JS, Degorce SL, Anjum R, Culshaw J, Davies RDM, Davies NL, Dillman KS, Dowling JE, Drew L, Ferguson AD, Groombridge SD, Halsall CT, Hudson JA, Lamont S, Lindsay NA, Marden SK, Mayo MF, Pease JE, Perkins DR, Pink JH, Robb GR, Rosen A, Shen M, McWhirter C, Wu D
J Med Chem 60 10071-10091 (2017)
Related entries: 5k72, 5k75, 5k76, 5k7i

Cited: 17 times
EuropePMC logo PMID: 29172502

Abstract

Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.

Reviews citing this publication (5)

  1. Understanding early TLR signaling through the Myddosome. Balka KR, De Nardo D. J Leukoc Biol 105 339-351 (2019)
  2. Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy. Singer JW, Fleischman A, Al-Fayoumi S, Mascarenhas JO, Yu Q, Agarwal A. Oncotarget 9 33416-33439 (2018)
  3. Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities. Weber ANR, Cardona Gloria Y, Çınar Ö, Reinhardt HC, Pezzutto A, Wolz OO. Cancer Immunol Immunother 67 1797-1807 (2018)
  4. IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies. Bennett J, Starczynowski DT. Curr Opin Hematol 29 8-19 (2022)
  5. MYD88 Mutations: Transforming the Landscape of IgM Monoclonal Gammopathies. Alcoceba M, García-Álvarez M, Medina A, Maldonado R, González-Calle V, Chillón MC, Sarasquete ME, González M, García-Sanz R, Jiménez C. Int J Mol Sci 23 5570 (2022)

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  1. Mitochondrial clearance and maturation of autophagosomes are compromised in LRRK2 G2019S familial Parkinson's disease patient fibroblasts. Korecka JA, Thomas R, Christensen DP, Hinrich AJ, Ferrari EJ, Levy SA, Hastings ML, Hallett PJ, Isacson O. Hum Mol Genet 28 3232-3243 (2019)
  2. Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs. Chen Y, Ning Y, Bai G, Tong L, Zhang T, Zhou J, Zhang H, Xie H, Ding J, Duan W. ACS Med Chem Lett 12 82-87 (2021)
  3. Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies. Gummadi VR, Boruah A, Ainan BR, Vare BR, Manda S, Gondle HP, Kumar SN, Mukherjee S, Gore ST, Krishnamurthy NR, Marappan S, Nayak SS, Nellore K, Balasubramanian WR, Bhumireddy A, Giri S, Gopinath S, Samiulla DS, Daginakatte G, Basavaraju A, Chelur S, Eswarappa R, Belliappa C, Subramanya HS, Booher RN, Ramachandra M, Samajdar S. ACS Med Chem Lett 11 2374-2381 (2020)
  4. Discovery of a Selective, Covalent IRAK1 Inhibitor with Antiproliferative Activity in MYD88 Mutated B-Cell Lymphoma. Hatcher JM, Yang G, Wang L, Ficarro SB, Buhrlage S, Wu H, Marto JA, Treon SP, Gray NS. ACS Med Chem Lett 11 2238-2243 (2020)
  5. Lowering Lipophilicity by Adding Carbon: AzaSpiroHeptanes, a logD Lowering Twist. Degorce SL, Bodnarchuk MS, Scott JS. ACS Med Chem Lett 10 1198-1204 (2019)
  6. Experimental free ligand conformations: a missing link in structure-based drug discovery. Chiarparin E, Packer MJ, Wilson DM. Future Med Chem 11 79-82 (2019)
  7. Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells. Nalairndran G, Chung I, Abdul Razack AH, Chung FF, Hii LW, Lim WM, Looi CK, Mai CW, Leong CO. J Cell Mol Med 25 8187-8200 (2021)
  8. Case Reports Genomic Alterations In Primary Cardiac Diffuse Large B Cell Lymphoma: A Case Report And Literature Review. Zhang J, Lin X, Li Y, Zhang R. Onco Targets Ther 12 9085-9092 (2019)
  9. Teaching and Learning Computational Drug Design: Student Investigations of 3D Quantitative Structure-Activity Relationships through Web Applications. Ragno R, Esposito V, Di Mario M, Masiello S, Viscovo M, Cramer RD. J Chem Educ 97 1922-1930 (2020)
  10. C-H Imidation of 7-Deazapurines. Sabat N, Poštová Slavětínská L, Klepetářová B, Hocek M. ACS Omega 3 4674-4678 (2018)
  11. BET inhibition targets ABC-DLBCL constitutive B-cell receptor signaling through PAX5. Oien DB, Sharma S, Hattersley MM, DuPont M, Criscione SW, Prickett L, Goeppert AU, Drew L, Yao Y, Zhang J, Chan HM. Blood Adv 7 5108-5121 (2023)
  12. Simplified Procedure for General Synthesis of Monosubstituted Piperazines-From a Batch Reaction Vessel to a Flow (Microwave) Reactor. Němečková D, Havránková E, Šimbera J, Ševčík R, Pazdera P. Molecules 25 E2168 (2020)


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