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

被引：52

作者：

Scott, James S. ^{[1
]}

Degorce, Sebastien L. ^{[1
]}

Anjum, Rana ^{[2
]}

Culshaw, Janet

Davies, Robert D. M. ^{[3
]}

Davies, Nichola L. ^{[1
]}

Dillman, Keith S. ^{[2
]}

Dowling, James E. ^{[2
]}

Drew, Lisa ^{[2
]}

Ferguson, Andrew D. ^{[2
]}

Groombridge, Sam D. ^{[3
]}

Halsall, Christopher T. ^{[3
]}

Hudson, Julian A. ^{[3
]}

Lamont, Scott ^{[1
]}

Lindsay, Nicola A. ^{[1
]}

Marden, Stacey K. ^{[4
]}

Mayo, Michele F. ^{[2
]}

Pease, J. Elizabeth ^{[1
]}

Perkins, David R. ^{[3
]}

Pink, Jennifer H. ^{[3
]}

Robb, Graeme R. ^{[1
]}

Rosen, Alan ^{[2
]}

Shen, Minhui ^{[2
]}

McWhirter, Claire ^{[1
]}

Wu, Dedong ^{[4
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Oncol, Cambridge CB4 0FZ, England

[2] AstraZeneca, IMED Biotech Unit, Oncol, Boston, MA 02451 USA

[3] AstraZeneca, IMED Biotech Unit, Oncol, Macclesfield SK10 4TG, Cheshire, England

[4] AstraZeneca, IMED Biotech Unit, Pharmaceut Sci, Boston, MA 02451 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 24期

关键词：

PYOGENIC BACTERIAL-INFECTIONS; L265P SOMATIC MUTATION; PART; MYD88; SERIES; IDENTIFICATION; PREVALENCE; IBRUTINIB; HUMANS; POTENT;

D O I：

10.1021/acs.jmedchem.7b01290

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 MYD88(L265P) diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-kappa B 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.

引用

页码：10071 / 10091

页数：21

共 47 条

[31] The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress [J].

O'Neill, Luke A. J. .

IMMUNOLOGICAL REVIEWS, 2008, 226 :10-18

[32] Pyogenic bacterial infections in humans with IRAK-4 deficiency [J].

Picard, C ;

Puel, A ;

Bonnet, M ;

Ku, CL ;

Bustamante, J ;

Yang, K ;

Soudais, C ;

Dupuis, S ;

Feinberg, J ;

Fieschi, C ;

Elbim, C ;

Hitchcock, R ;

Lammas, D ;

Davies, G ;

Al-Ghonaium, A ;

Al-Rayes, H ;

Al-Jumaah, S ;

Al-Hajjar, S ;

Al-Mohsen, IZ ;

Frayha, HH ;

Rucker, R ;

Hawn, TR ;

Aderem, A ;

Tufenkeji, H ;

Haraguchi, S ;

Day, NK ;

Good, RA ;

Gougerot-Pocidalo, MA ;

Ozinsky, A ;

Casanova, JL .

SCIENCE, 2003, 299 (5615) :2076-2079

[33] Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4 [J].

Powers, JP ;

Li, SY ;

Jaen, JC ;

Liu, JQ ;

Walker, NPC ;

Wang, ZL ;

Wesche, H .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (11) :2842-2845

[34]

Romero D. L., 2012, IRAK Inhibitors and Uses Thereof, Patent No. [WO2012097013 A1, 2012097013]

[35] Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors [J].

Seganish, W. Michael ;

Fischmann, Thierry O. . ;

Sherborne, Brad ;

Matasi, Julius ;

Lavey, Brian ;

McElroy, William T. ;

Tulshian, Deen ;

Tata, James ;

Sondey, Christopher ;

Garlisi, Charles G. ;

Devito, Kristine ;

Fossetta, James ;

Lundell, Daniel ;

Niu, Xiaoda .

ACS MEDICINAL CHEMISTRY LETTERS, 2015, 6 (08) :942-947

[36] Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 [J].

Seganish, W. Michael ;

McElroy, William T. ;

Herr, R. Jason ;

Brumfield, Stephanie ;

Greenlee, William J. ;

Harding, James ;

Komanduri, Venukrishnan ;

Matasi, Julius ;

Prakash, Koraboina Chandra ;

Tulshian, Deen ;

Yang, Jinhai ;

Yet, Larry ;

Devito, Kristine ;

Fossetta, James ;

Garlisi, Charles G. ;

Lundell, Daniel ;

Niu, Xiaoda ;

Sondey, Christopher .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (16) :3203-3207

[37] Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia [J].

Sehn, LH ;

Donaldson, J ;

Chhanabhai, M ;

Fitzgerald, C ;

Gill, K ;

Klasa, R ;

MacPherson, N ;

O'Reilly, S ;

Spinelli, JJ ;

Sutherland, J ;

Wilson, KS ;

Gascoyne, RD ;

Connors, JM .

JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (22) :5027-5033

[38] MYD88 L265P Mutation Is a Possible Unfavorable Prognostic Factor in Patients with Diffuse B-Cell Lymphoma [J].

Sidorova, Anna A. ;

Zvonkov, Eugene E. ;

Sudarikov, Andrey B. ;

Severina, Nataliya A. ;

Kovrigina, Alla M. ;

Troitskaya, Vera V. ;

Savchenko, Valeri G. .

BLOOD, 2015, 126 (23)

[39] Cancer statistics, 2013 [J].

Siegel, Rebecca ;

Naishadham, Deepa ;

Jemal, Ahmedin .

CA-A CANCER JOURNAL FOR CLINICIANS, 2013, 63 (01) :11-30

[40] MYD88 L265P Somatic Mutation in Waldenstrom's Macroglobulinemia [J].

Treon, Steven P. ;

Xu, Lian ;

Yang, Guang ;

Zhou, Yangsheng ;

Liu, Xia ;

Cao, Yang ;

Sheehy, Patricia ;

Manning, Robert J. ;

Patterson, Christopher J. ;

Tripsas, Christina ;

Arcaini, Luca ;

Pinkus, Geraldine S. ;

Rodig, Scott J. ;

Sohani, Aliyah R. ;

Harris, Nancy Lee ;

Laramie, Jason M. ;

Skifter, Donald A. ;

Lincoln, Stephen E. ;

Hunter, Zachary R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (09) :826-833

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