A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells.
Although chemokine and growth factor receptors are attractive and popular targets for cancer therapeutic intervention, structure-based targeting of the ligands themselves is generally not considered practical. New evidence indicates that a notable exception to this is macrophage migration inhibitory factor (MIF). MIF, an autocrine- and paracrine-acting cytokine/growth factor, plays a pivotal role in both the initiation and maintenance of neoplastic diseases. MIF possesses a nonphysiologic enzymatic activity that is evolutionarily well-conserved. Although small molecule antagonists of MIFs enzymatic active site have been reported to inhibit biological activities of MIF, universally high IC(50)s have limited their clinical appeal. Using a computational virtual screening strategy, we have identified a unique small molecule inhibitor that serves as a suicide substrate for MIF, resulting in the covalent modification of the catalytically active NH(2)-terminal proline. Our studies further reveal that this compound, 4-iodo-6-phenylpyrimidine (4-IPP), is approximately 5x to 10x times more potent in blocking MIF-dependent catalysis and lung adenocarcinoma cell migration and anchorage-independent growth than the prototypical MIF inhibitor, ISO-1. Finally, using an in silico combinatorial optimization strategy, we have identified four unique congeners of 4-IPP that exhibit MIF inhibitory activity at concentrations 10x to 20x lower than that of parental 4-IPP.
Winner
Millicent
M
Molecular Targets Program, University of Louisville, KY, USA.
Meier
Jason
J
Zierow
Swen
S
Rendon
Beatriz E
BE
Crichlow
Gregg V
GV
Riggs
Randall
R
Bucala
Richard
R
Leng
Lin
L
Smith
Ned
N
Lolis
Elias
E
Trent
John O
JO
Mitchell
Robert A
RA
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011743:Pyrimidines / Q000494:pharmacology*
C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; C532251:4-iodo-6-phenylpyrimidine; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D011743:Pyrimidines; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
Biochemistry. 1999 Sep 28;38(39):12841-9
10504254
Immunity. 2006 Oct;25(4):595-606
17045821
Methods Enzymol. 1997;276:307-26
27754618
J Med Chem. 2001 Feb 15;44(4):540-7
11170644
J Biol Chem. 2002 Jul 12;277(28):24976-82
11997397
J Biol Chem. 2005 Nov 4;280(44):36541-4
16115897
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5191-6
8643551
J Exp Med. 2003 Jun 2;197(11):1467-76
12782713
Biochemistry. 1994 Nov 29;33(47):14144-55
7947826
Mol Med. 1996 Jan;2(1):143-9
8900542
J Biol Chem. 2005 Jun 17;280(24):23066-72
15840582
J Biol Chem. 2006 Nov 10;281(45):34381-93
16963454
J Med Chem. 2007 Apr 19;50(8):1993-7
17385848
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
15299926
EMBO J. 1998 Jul 1;17(13):3534-41
9649424
Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
9757107
J Biol Chem. 2007 Oct 12;282(41):29910-8
17709373
J Immunol. 2006 Dec 15;177(12):8730-9
17142775
Acta Crystallogr D Biol Crystallogr. 2004 Mar;60(Pt 3):432-8
14993666
J Biol Chem. 2007 Aug 10;282(32):23089-95
17526494