From identification of the BTK kinase to effective management of leukemia.
BTK is a cytoplasmic protein-tyrosine kinase, whose corresponding gene was isolated in the early 1990s. BTK was initially identified by positional cloning of the gene causing X-linked agammaglobulinemia and independently in a search for new kinases. Given the phenotype of affected patients, namely lack of B-lymphocytes and plasma cells with the ensuing inability to mount humoral immune responses, BTK inhibitors were anticipated to have beneficial effects on antibody-mediated pathologies, such as autoimmunity. In contrast to, for example, the SRC-family of cytoplasmic kinases, there was no obvious way in which structural alterations would yield constitutively active forms of BTK, and such mutations were also not found in leukemias or lymphomas. In 2007, the first efficient inhibitor, ibrutinib, was reported and soon became approved both in the United States and in Europe for the treatment of three B-cell malignancies, mantle cell lymphoma, chronic lymphocytic leukemia and Waldenström's macroglobulinemia. Over the past few years, additional inhibitors have been developed, with acalabrutinib being more selective, and recently demonstrating fewer clinical adverse effects. The antitumor mechanism is also not related to mutations in BTK. Instead tumor residency in lymphoid organs is inhibited, making these drugs highly versatile. BTK is one of the only 10 human kinases that carry a cysteine in the adenosine triphosphate-binding cleft. As this allows for covalent, irreversible inhibitor binding, it provides these compounds with a highly advantageous character. This quality may be crucial and bodes well for the future of BTK-modifying medicines, which have been estimated to reach annual multi-billion dollar sales in the future.
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
C I E
CI
Smith
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
Genomics. 1990 Feb;6(2):238-42
2307467
Science. 1996 Feb 9;271(5250):822-5
8629002
N Engl J Med. 2016 Jan 28;374(4):323-32
26641137
Bioessays. 2001 May;23(5):436-46
11340625
Lancet. 1991 Jul 20;338(8760):162-6
1712881
N Engl J Med. 2016 Jan 28;374(4):311-22
26639348
Oncotarget. 2016 May 3;7(18):26346-60
27029059
Science. 1993 Jul 16;261(5119):355-8
8332900
Hum Mutat. 2006 Dec;27(12):1209-17
16969761
J Pharmacol Exp Ther. 2013 Aug;346(2):219-28
23709115
Immunol Rev. 2009 Mar;228(1):58-73
19290921
Lancet. 2016 Feb 20;387(10020):770-8
26673811
Nat Commun. 2016 May 20;7:11589
27199251
Expert Rev Clin Immunol. 2013 Dec;9(12):1205-21
24215410
N Engl J Med. 2015 Apr 9;372(15):1430-40
25853747
Blood. 2016 Jan 28;127(4):411-9
26542378
Cell. 2009 Mar 20;136(6):1110-21
19303853
Proc Natl Acad Sci U S A. 2002 May 14;99(10):6955-60
12011454
Adv Immunol. 1995;59:135-223
7484460
J Clin Oncol. 2013 Jan 1;31(1):88-94
23045577
N Engl J Med. 2013 Aug 8;369(6):507-16
23782157
Leukemia. 2016 Apr;30(4):833-43
26582643
Mol Cell Biol. 1999 Jun;19(6):4405-13
10330180
Mol Cell. 1998 May;1(6):831-40
9660966
Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80
20615965
Lancet. 1971 Oct 9;2(7728):791-4
4106608
J Exp Med. 2003 Jul 7;198(1):91-8
12835482
Blood. 2015 Apr 2;125(14):2306-9
25838279
ChemMedChem. 2007 Jan;2(1):58-61
17154430
Science. 2014 Jan 17;343(6168):294-7
24436419
Blood. 2016 Jun 23;127(25):3237-52
27143257
Blood. 2016 Mar 24;127(12):1559-63
26764355
Cell. 1993 Jan 29;72(2):279-90
8425221
Hum Mutat. 2015 Jun;36(6):638-47
25777788
Curr Top Microbiol Immunol. 2016;393:143-174
26369772
N Engl J Med. 2013 Jul 4;369(1):32-42
23782158
Adv Genet. 2008;64:51-80
19161832
Cancer Res. 2016 Apr 15;76(8):2125-36
26880800
N Engl J Med. 2014 Jun 12;370(24):2352-4
24869597
Int J Cancer. 1983 Oct 15;32(4):431-5
6413431
Immunol Today. 1996 Nov;17(11):495-6
8961623
Ann Clin Res. 1987;19(4):220-9
3314648
J Exp Med. 1996 Jul 1;184(1):31-40
8691147
Blood. 2012 Mar 15;119(11):2590-4
22279054
Biochem J. 1937 Feb;31(2):313-7
16746340
EMBO J. 1987 Aug;6(8):2273-80
3117531
J Biol Chem. 2006 Jun 30;281(26):18201-7
16644721
Blood. 2015 Jan 8;125(2):242-8
25355819
EMBO J. 1985 Sep;4(9):2217-24
3000764
Blood. 2012 Feb 2;119(5):1182-9
22180443
JAMA Oncol. 2015 Apr;1(1):80-7
26182309
Lancet Oncol. 2015 Feb;16(2):169-76
25555420
J Biol Chem. 1999 Apr 2;274(14):9587-99
10092645
Lancet Oncol. 2014 Aug;15(9):1019-26
25042202
Clin Exp Immunol. 2015 Feb;179(2):146-60
25384609
Immunol Today. 1995 Oct;16(10):460-5
7576047
FEBS Lett. 1994 Aug 22;350(2-3):263-5
8070576
Immunol Rev. 1994 Apr;138:159-83
8070814
Immunity. 1995 May;2(5):451-60
7538439
Blood. 2014 Feb 20;123(8):1207-13
24311722
Trends Immunol. 2016 Mar;37(3):208-220
26858199
EMBO J. 2001 Oct 15;20(20):5692-702
11598012
Haematologica. 2016 Jul;101(7):e295-8
27151992
FEBS Lett. 2005 Aug 1;579(19):4131-7
16023106
EMBO J. 1996 Nov 15;15(22):6241-50
8947047
Science. 1993 Jul 16;261(5119):358-61
8332901
Oncogene. 1996 Nov 7;13(9):1955-64
8934542
J Exp Med. 2000 May 15;191(10):1745-54
10811867
Proc Natl Acad Sci U S A. 2016 May 3;113(18):5065-70
27099294
Open J Hematol. 2012;3(S1):
22844583
Leukemia. 2015 Apr;29(4):895-900
25189416
Lancet Oncol. 2016 Jan;17(1):48-56
26640039
Scand J Immunol. 2015 Sep;82(3):208-17
26111359
Nucleic Acids Res. 1998 Jan 1;26(1):242-7
9399844
Pediatr Res. 2002 Feb;51(2):159-68
11809909
Cancer Discov. 2014 Sep;4(9):1022-35
25082755
Aust J Exp Biol Med Sci. 1969 Dec;47(6):759-61
5377812
Blood. 2011 Jun 9;117(23):6287-96
21422473
Adv Genet. 1997;35:57-115
9348646
PLoS One. 2012;7(5):e35640
22574122
Hum Genet. 1989 Dec;84(1):19-21
2575070
Mol Cell Biol. 2013 Aug;33(16):3214-26
23754751
Immunol Rev. 2005 Feb;203:200-15
15661031
Nature. 1993 Jan 21;361(6409):226-33
8380905
J Exp Med. 2000 May 15;191(10):1735-44
10811866
Blood. 2008 May 1;111(9):4617-26
18292289
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12530-4
7809072
N Engl J Med. 2014 Jun 12;370(24):2286-94
24869598
Lancet. 1963 Apr 20;1(7286):859-60
13976296
Praxis. 1947 Apr 17;36(16):280
20241408
Nature. 1984 Apr 26-May 2;308(5962):858-60
6609313
Haematologica. 2016 Dec;101(12):1573-1580
27198718
Annu Rev Immunol. 2009;27:199-227
19302039
N Engl J Med. 2016 Jan 28;374(4):386-8
26816016
Lancet Oncol. 2014 Jan;15(1):48-58
24332241
Leukemia. 2017 Jan;31(1):177-185
27282255