Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit

被引：22

作者：

Qiu, Hui ^{[1
]}

Liu-Bujalski, Lesley ^{[1
]}

Caldwell, Richard D. ^{[1
]}

Follis, Ariele Viacava ^{[1
]}

Gardberg, Anna ^{[2
]}

Goutopoulos, Andreas ^{[1
]}

Grenningloh, Roland ^{[1
]}

Head, Jared ^{[1
]}

Johnson, Theresa ^{[1
]}

Jones, Reinaldo ^{[1
]}

Mochalkin, Igor ^{[1
]}

Morandi, Federica ^{[3
]}

Neagh, Constantin ^{[1
]}

Sherer, Brian ^{[1
]}

机构：

[1] EMD Serono Res & Dev Inst Inc, 45A Middlesex Turnpike, Billerica, MA 01821 USA

[2] Constellat Pharmaceut, 215 First St,Suite 200, Cambridge, MA 02142 USA

[3] F Hoffmann La Roche & Cie AG, Konzem Hauptsitz, Grenzacherstr 124, CH-4070 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 17期

关键词：

Covalent; Irreversible; BTK inhibitor; Fragment; TYROSINE KINASE INHIBITORS; ACALABRUTINIB ACP-196; B-CELL; IBRUTINIB; ARTHRITIS; DESIGN;

D O I：

10.1016/j.bmcl.2018.07.008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.

引用

页码：2939 / 2944

页数：6

共 17 条

[1] Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile
Barf, Tjeerd
Covey, Todd
Izumi, Raquel
van de Kar, Bas
Gulrajani, Michael
van Lith, Bart
van Hoek, Maaike
de Zwart, Edwin
Mittag, Diana
Demont, Dennis
Verkaik, Saskia
Krantz, Fanny
Pearson, Paul G.
Ulrich, Roger
Kaptein, Allard
[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2017, 363 (02) : 240 - 252
[2] Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia
Byrd, J. C.
Brown, J. R.
O'Brien, S.
Barrientos, J. C.
Kay, N. E.
Reddy, N. M.
Coutre, S.
Tam, C. S.
Mulligan, S. P.
Jaeger, U.
Devereux, S.
Barr, P. M.
Furman, R. R.
Kipps, T. J.
Cymbalista, F.
Pocock, C.
Thornton, P.
Caligaris-Cappio, F.
Robak, T.
Delgado, J.
Schuster, S. J.
Montillo, M.
Schuh, A.
de Vos, S.
Gill, D.
Bloor, A.
Dearden, C.
Moreno, C.
Jones, J. J.
Chu, A. D.
Fardis, M.
McGreivy, J.
Clow, F.
James, D. F.
Hillmen, P.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (03) : 213 - 223
[3] Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis
Di Paolo, Julie A.
Huang, Tao
Balazs, Mercedesz
Barbosa, James
Barck, Kai H.
Bravo, Brandon J.
Carano, Richard A. D.
Darrow, James
Davies, Douglas R.
DeForge, Laura E.
Diehl, Lauri
Ferrando, Ronald
Gallion, Steven L.
Giannetti, Anthony M.
Gribling, Peter
Hurez, Vincent
Hymowitz, Sarah G.
Jones, Randall
Kropf, Jeffrey E.
Lee, Wyne P.
Maciejewski, Patricia M.
Mitchell, Scott A.
Rong, Hong
Staker, Bart L.
Whitney, J. Andrew
Yeh, Sherry
Young, Wendy B.
Yu, Christine
Zhang, Juan
Reif, Karin
Currie, Kevin S.
[J]. NATURE CHEMICAL BIOLOGY, 2011, 7 (01) : 41 - 50
[4] The two novel BTK-inhibitors M2951 and M7583 show in vivo anti-tumor activity in pre-clinical models of B cell lymphoma
Gaudio, Eugenio
Tarantelli, Chiara
Zucca, Emanuele
Rossi, Davide
Stathis, Anastasios
Bertoni, Francesco
[J]. CANCER RESEARCH, 2017, 77
[5] Structural Modifications that Alter the P-Glycoprotein Efflux Properties of Compounds
Hitchcock, Stephen A.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (11) : 4877 - 4895
[6] Bruton's Tyrosine Kinase Inhibitors: Approaches to Potent and Selective Inhibition, Preclinical and Clinical Evaluation for Inflammatory Diseases and B Cell Malignancies
Lou, Yan
Owens, Timothy D.
Kuglstatter, Andreas
Kondru, Rama K.
Goldstein, David M.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (10) : 4539 - 4550
[7] Investigational Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis
Norman, Peter
[J]. EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2016, 25 (08) : 891 - 899
[8] Bioisosterism: A rational approach in drug design
Patani, GA
LaVoie, EJ
[J]. CHEMICAL REVIEWS, 1996, 96 (08) : 3147 - 3176
[9] Qiu H, BIOORG MED CHE UNPUB
[10] Qiu H, 36 NAT MED CHEM S 20

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