| Structural highlights
Function
[M3K5_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Publication Abstract from PubMed
Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar potency in a cellular assay, high selectivity when tested against kinase and broad pharmacology screening panels, and attractive physicochemical properties. The compounds we describe are attractive tool compounds to inform the therapeutic potential of ASK1 inhibition.
Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors.,Lovering F, Morgan P, Allais C, Aulabaugh A, Brodfuehrer J, Chang J, Coe J, Ding W, Dowty H, Fleming M, Frisbie R, Guzova J, Hepworth D, Jasti J, Kortum S, Kurumbail R, Mohan S, Papaioannou N, Strohbach JW, Vincent F, Lee K, Zapf CW Eur J Med Chem. 2017 Dec 15;145:606-621. doi: 10.1016/j.ejmech.2017.12.041. PMID:29348070[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wang XS, Diener K, Jannuzzi D, Trollinger D, Tan TH, Lichenstein H, Zukowski M, Yao Z. Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. J Biol Chem. 1996 Dec 6;271(49):31607-11. PMID:8940179
- ↑ Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997 Jan 3;275(5296):90-4. PMID:8974401
- ↑ Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998 May 1;17(9):2596-606. PMID:9564042 doi:10.1093/emboj/17.9.2596
- ↑ Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol Cell. 1998 Sep;2(3):389-95. PMID:9774977
- ↑ Zhang L, Chen J, Fu H. Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8511-5. PMID:10411906
- ↑ Hatai T, Matsuzawa A, Inoshita S, Mochida Y, Kuroda T, Sakamaki K, Kuida K, Yonehara S, Ichijo H, Takeda K. Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. J Biol Chem. 2000 Aug 25;275(34):26576-81. PMID:10849426 doi:10.1074/jbc.M003412200
- ↑ Liu H, Nishitoh H, Ichijo H, Kyriakis JM. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol Cell Biol. 2000 Mar;20(6):2198-208. PMID:10688666
- ↑ Morita K, Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, Ichijo H. Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress. EMBO J. 2001 Nov 1;20(21):6028-36. PMID:11689443 doi:10.1093/emboj/20.21.6028
- ↑ Sayama K, Hanakawa Y, Shirakata Y, Yamasaki K, Sawada Y, Sun L, Yamanishi K, Ichijo H, Hashimoto K. Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation. J Biol Chem. 2001 Jan 12;276(2):999-1004. PMID:11029458 doi:10.1074/jbc.M003425200
- ↑ Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 2001 Feb;21(3):893-901. PMID:11154276 doi:10.1128/MCB.21.3.893-901.2001
- ↑ Takeda K, Matsuzawa A, Nishitoh H, Tobiume K, Kishida S, Ninomiya-Tsuji J, Matsumoto K, Ichijo H. Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation. EMBO Rep. 2004 Feb;5(2):161-6. Epub 2004 Jan 16. PMID:14749717 doi:10.1038/sj.embor.7400072
- ↑ Tobiume K, Saitoh M, Ichijo H. Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer. J Cell Physiol. 2002 Apr;191(1):95-104. PMID:11920685 doi:10.1002/jcp.10080
- ↑ Yuan ZQ, Feldman RI, Sussman GE, Coppola D, Nicosia SV, Cheng JQ. AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance. J Biol Chem. 2003 Jun 27;278(26):23432-40. Epub 2003 Apr 15. PMID:12697749 doi:10.1074/jbc.M302674200
- ↑ Subramanian RR, Zhang H, Wang H, Ichijo H, Miyashita T, Fu H. Interaction of apoptosis signal-regulating kinase 1 with isoforms of 14-3-3 proteins. Exp Cell Res. 2004 Apr 1;294(2):581-91. PMID:15023544 doi:10.1016/j.yexcr.2003.12.009
- ↑ Goldman EH, Chen L, Fu H. Activation of apoptosis signal-regulating kinase 1 by reactive oxygen species through dephosphorylation at serine 967 and 14-3-3 dissociation. J Biol Chem. 2004 Mar 12;279(11):10442-9. Epub 2003 Dec 19. PMID:14688258 doi:10.1074/jbc.M311129200
- ↑ Noguchi T, Takeda K, Matsuzawa A, Saegusa K, Nakano H, Gohda J, Inoue J, Ichijo H. Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death. J Biol Chem. 2005 Nov 4;280(44):37033-40. Epub 2005 Aug 29. PMID:16129676 doi:10.1074/jbc.M506771200
- ↑ Zhao Y, Conze DB, Hanover JA, Ashwell JD. Tumor necrosis factor receptor 2 signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates mitogen-activated protein kinase signaling. J Biol Chem. 2007 Mar 16;282(11):7777-82. Epub 2007 Jan 12. PMID:17220297 doi:10.1074/jbc.M609146200
- ↑ Lovering F, Morgan P, Allais C, Aulabaugh A, Brodfuehrer J, Chang J, Coe J, Ding W, Dowty H, Fleming M, Frisbie R, Guzova J, Hepworth D, Jasti J, Kortum S, Kurumbail R, Mohan S, Papaioannou N, Strohbach JW, Vincent F, Lee K, Zapf CW. Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors. Eur J Med Chem. 2017 Dec 15;145:606-621. doi: 10.1016/j.ejmech.2017.12.041. PMID:29348070 doi:http://dx.doi.org/10.1016/j.ejmech.2017.12.041
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