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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Review Article

Small Molecules as LIM Kinase Inhibitors

Author(s): Syed N.A. Bukhari*, Michael A. Tandiary, Mohammad M. Al-Sanea, Mohamed A. Abdelgawad, Chin F. Chee and Muhammad A. Hussain

Volume 29, Issue 17, 2022

Published on: 18 January, 2022

Page: [2995 - 3027] Pages: 33

DOI: 10.2174/0929867328666211026120335

Price: $65

Abstract

LIMK1 and LIMK2 are involved in the regulation of cellular functions that depend on the dynamics of actin cytoskeleton. Disregulation of LIM kinases has been associated with diseases, such as tumor progression and metastasis, viral infection, and ocular diseases. Motivated by this, numerous studies have been carried out to discover small organic molecules capable of inhibiting LIM kinase effectively and selectively. In this review, a comprehensive survey of small organic molecules for LIM kinase inhibitors is reported, together with SAR study results, and the synthesis of these inhibitors.

Keywords: Cytoskeleton, thiazole, thienopyridine derivatives, thienopyrimidine, synthesis, LIM kinase.

« Previous Next »
[1]
Hanks, S.K.; Quinn, A.M.; Hunter, T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science, 1988, 241(4861), 42-52.
[http://dx.doi.org/10.1126/science.3291115] [PMID: 3291115]
[2]
(a) Mizuno, K.; Okano, I.; Ohashi, K.; Nunoue, K.; Kuma, K.; Miyata, T.; Nakamura, T. Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif. Oncogene, 1994, 9(6), 1605-1612.
[PMID: 8183554]
(b) Nunoue, K.; Ohashi, K.; Okano, I.; Mizuno, K. LIMK-1 and LIMK-2, two members of a LIM motif-containing protein kinase family. Oncogene, 1995, 11(4), 701-710.
[PMID: 7651734]
[3]
(a) Arber, S.; Barbayannis, F.A.; Hanser, H.; Schneider, C.; Stanyon, C.A.; Bernard, O.; Caroni, P. Regulation of actin dynamics through phosphorylation of cofilin by LIMkinase. Nature, 1998, 393(6687), 805-809.
[http://dx.doi.org/10.1038/31729] [PMID: 9655397]
(b) Yang, N.; Higuchi, O.; Ohashi, K.; Nagata, K.; Wada, A.; Kangawa, K.; Nishida, E.; Mizuno, K. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature, 1998, 393(6687), 809-812.
[http://dx.doi.org/10.1038/31735] [PMID: 9655398]
[4]
Rodriguez, O.C.; Schaefer, A.W.; Mandato, C.A.; Forscher, P.; Bement, W.M.; Waterman-Storer, C.M. Conserved microtubule-actin interactions in cell movement and morphogenesis. Nat. Cell Biol., 2003, 5(7), 599-609.
[http://dx.doi.org/10.1038/ncb0703-599] [PMID: 12833063]
[5]
Maekawa, M.; Ishizaki, T.; Boku, S.; Watanabe, N.; Fujita, A.; Iwamatsu, A.; Obinata, T.; Ohashi, K.; Mizuno, K.; Narumiya, S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science, 1999, 285(5429), 895-898.
[http://dx.doi.org/10.1126/science.285.5429.895] [PMID: 10436159]
[6]
(a) Edwards, D.C.; Sanders, L.C.; Bokoch, G.M.; Gill, G.N. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat. Cell Biol., 1999, 1(5), 253-259.
[http://dx.doi.org/10.1038/12963] [PMID: 10559936]
(b) Dan, C.; Kelly, A.; Bernard, O.; Minden, A. Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin. J. Biol. Chem., 2001, 276(34), 32115-32121.
[http://dx.doi.org/10.1074/jbc.M100871200] [PMID: 11413130]
[7]
(a) DeVita, V.T., Jr; Young, R.C.; Canellos, G.P. Combination versus single agent chemotherapy: a review of the basis for selection of drug treatment of cancer. Cancer, 1975, 35(1), 98-110.
[http://dx.doi.org/10.1002/1097-0142(197501)35:1<98::AID-CNCR2820350115>3.0.CO;2-B] [PMID: 162854]
(b) Guan, X. Cancer metastases: Challenges and opportunities. Acta Pharm. Sin. B, 2015, 5(5), 402-418.
[http://dx.doi.org/10.1016/j.apsb.2015.07.005] [PMID: 26579471]
[8]
Yamaguchi, H.; Condeelis, J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim. Biophys. Acta, 2007, 1773(5), 642-652.
[http://dx.doi.org/10.1016/j.bbamcr.2006.07.001] [PMID: 16926057]
[9]
(a) Okamoto, I.; Pirker, C.; Bilban, M.; Berger, W.; Losert, D.; Marosi, C.; Haas, O.A.; Wolff, K.; Pehamberger, H. Seven novel and stable translocations associated with oncogenic gene expression in malignant melanoma. Neoplasia, 2005, 7(4), 303-311.
[http://dx.doi.org/10.1593/neo.04514] [PMID: 15967107]
(b) Bagheri-Yarmand, R.; Mazumdar, A.; Sahin, A.A.; Kumar, R. LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system. Int. J. Cancer, 2006, 118(11), 2703-2710.
[http://dx.doi.org/10.1002/ijc.21650] [PMID: 16381000]
(c) Yoshioka, K.; Foletta, V.; Bernard, O.; Itoh, K. A role for LIM kinase in cancer invasion. Proc. Natl. Acad. Sci. USA, 2003, 100(12), 7247-7252.
[http://dx.doi.org/10.1073/pnas.1232344100] [PMID: 12777619]
(d) Davila, M.; Frost, A.R.; Grizzle, W.E.; Chakrabarti, R. LIM kinase 1 is essential for the invasive growth of prostate epithelial cells: Implications in prostate cancer. J. Biol. Chem., 2003, 278(38), 36868-36875.
[http://dx.doi.org/10.1074/jbc.M306196200] [PMID: 12821664]
(e) Dan, S.; Tsunoda, T.; Kitahara, O.; Yanagawa, R.; Zembutsu, H.; Katagiri, T.; Yamazaki, K.; Nakamura, Y.; Yamori, T. An integrated database of chemosensitivity to 55 anticancer drugs and gene expression profiles of 39 human cancer cell lines. Cancer Res., 2002, 62(4), 1139-1147.
[PMID: 11861395]
[10]
Wu, P.; Nielsen, T.E.; Clausen, M.H. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci., 2015, 36(7), 422-439.
[http://dx.doi.org/10.1016/j.tips.2015.04.005] [PMID: 25975227]
[11]
(a) Manetti, F. Recent advances in the rational design and development of LIM kinase inhibitors are not enough to enter clinical trials. Eur. J. Med. Chem., 2018, 155, 445-458.
[http://dx.doi.org/10.1016/j.ejmech.2018.06.016] [PMID: 29908439]
(b) Boland, S.; Bourin, A.; Alen, J.; Geraets, J.; Schroeders, P.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Vanormelingen, J.; Fransen, S.; Van de Velde, S.; Defert, O. Design, synthesis and biological characterization of selective LIMK inhibitors. Bioorg. Med. Chem. Lett., 2015, 25(18), 4005-4010.
[http://dx.doi.org/10.1016/j.bmcl.2015.07.009] [PMID: 26233434]
[12]
Ross-Macdonald, P.; de Silva, H.; Guo, Q.; Xiao, H.; Hung, C-Y.; Penhallow, B.; Markwalder, J.; He, L.; Attar, R.M.; Lin, T-A.; Seitz, S.; Tilford, C.; Wardwell-Swanson, J.; Jackson, D. Identification of a nonkinase target mediating cytotoxicity of novel kinase inhibitors. Mol. Cancer Ther., 2008, 7(11), 3490-3498.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0826] [PMID: 19001433]
[13]
He, L.; Seitz, S.P.; Trainor, G.L.; Tortolani, D.; Vaccaro, W.; Poss, M.; Tarby, C.M.; Tokarski, J.S.; Penhallow, B.; Hung, C.Y.; Attar, R.; Lin, T.A. Modulation of cofilin phosphorylation by inhibition of the Lim family kinases. Bioorg. Med. Chem. Lett., 2012, 22(18), 5995-5998.
[http://dx.doi.org/10.1016/j.bmcl.2012.07.002] [PMID: 22902653]
[14]
(a) Røsok, O.; Pedeutour, F.; Ree, A.H.; Aasheim, H-C. Identification and characterization of TESK2, a novel member of the LIMK/TESK family of protein kinases, predominantly expressed in testis. Genomics, 1999, 61(1), 44-54.
[http://dx.doi.org/10.1006/geno.1999.5922] [PMID: 10512679]
(b) Toshima, J.; Ohashi, K.; Okano, I.; Nunoue, K.; Kishioka, M.; Kuma, K.; Miyata, T.; Hirai, M.; Baba, T.; Mizuno, K. Identification and characterization of a novel protein kinase, TESK1, specifically expressed in testicular germ cells. J. Biol. Chem., 1995, 270(52), 31331-31337.
[http://dx.doi.org/10.1074/jbc.270.52.31331] [PMID: 8537404]
[15]
Charles, M.D.; Brookfield, J.L.; Ekwuru, T.C.; Stockley, M.; Dunn, J.; Riddick, M.; Hammonds, T.; Trivier, E.; Greenland, G.; Wong, A.C.; Cheasty, A.; Boyd, S.; Crighton, D.; Olson, M.F. Discovery, development, and SAR of aminothiazoles as LIMK inhibitors with cellular anti-invasive properties. J. Med. Chem., 2015, 58(20), 8309-8313.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01242] [PMID: 26356364]
[16]
Harrison, B.A.; Whitlock, N.A.; Voronkov, M.V.; Almstead, Z.Y.; Gu, K.J.; Mabon, R.; Gardyan, M.; Hamman, B.D.; Allen, J.; Gopinathan, S.; McKnight, B.; Crist, M.; Zhang, Y.; Liu, Y.; Courtney, L.F.; Key, B.; Zhou, J.; Patel, N.; Yates, P.W.; Liu, Q.; Wilson, A.G.E.; Kimball, S.D.; Crosson, C.E.; Rice, D.S.; Rawlins, D.B. Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma. J. Med. Chem., 2009, 52(21), 6515-6518.
[http://dx.doi.org/10.1021/jm901226j] [PMID: 19831390]
[17]
Harrison, B.A.; Almstead, Z.Y.; Burgoon, H.; Gardyan, M.; Goodwin, N.C.; Healy, J.; Liu, Y.; Mabon, R.; Marinelli, B.; Samala, L.; Zhang, Y.; Stouch, T.R.; Whitlock, N.A.; Gopinathan, S.; McKnight, B.; Wang, S.; Patel, N.; Wilson, A.G.E.; Hamman, B.D.; Rice, D.S.; Rawlins, D.B. Discovery and development of LX7101, a dual LIM-Kinase and ROCK inhibitor for the treatment of glaucoma. ACS Med. Chem. Lett., 2014, 6(1), 84-88.
[http://dx.doi.org/10.1021/ml500367g] [PMID: 25589936]
[18]
Goodwin, N.C.; Cianchetta, G.; Burgoon, H.A.; Healy, J.; Mabon, R.; Strobel, E.D.; Allen, J.; Wang, S.; Hamman, B.D.; Rawlins, D.B. Discovery of a type 3 inhibitor of LIM Kinase 2 that binds in a DFG-out conformation. ACS Med. Chem. Lett., 2014, 6(1), 53-57.
[http://dx.doi.org/10.1021/ml500242y] [PMID: 25589930]
[19]
Sleebs, B.E.; Levit, A.; Street, I.P.; Falk, H.; Hammonds, T.; Wong, A.C.; Charles, M.D.; Olson, M.F.; Baell, J.B. Identification of 3-aminothieno[2,3-b]pyridine-2-carboxamides and 4-aminobenzothieno[3,2-d]pyrimidines as LIMK1 inhibitors. MedChemComm, 2011, 2, 977-981.
[http://dx.doi.org/10.1039/c1md00137j]
[20]
Sleebs, B.E.; Nikolakopoulos, G.; Street, I.P.; Falk, H.; Baell, J.B. Identification of 5,6-substituted 4-aminothieno[2,3-d]pyrimidines as LIMK1 inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(19), 5992-5994.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.050] [PMID: 21852129]
[21]
(a) Mashiach-Farkash, E.; Rak, R.; Elad-Sfadia, G.; Haklai, R.; Carmeli, S.; Kloog, Y.; Wolfson, H.J. Computer-based identification of a novel LIMK1/2 inhibitor that synergizes with salirasib to destabilize the actin cytoskeleton. Oncotarget, 2012, 3(6), 629-639.
[http://dx.doi.org/10.18632/oncotarget.525] [PMID: 22776759]
(b) Rak, R.; Haklai, R.; Elad-Tzfadia, G.; Wolfson, H.J.; Carmeli, S.; Kloog, Y. Novel LIMK2 inhibitor blocks Panc-1 tumor growth in a mouse xenograft model. Oncoscience, 2014, 1(1), 39-48.
[http://dx.doi.org/10.18632/oncoscience.7] [PMID: 25593987]
[22]
Prudent, R.; Vassal-Stermann, E.; Nguyen, C-H.; Pillet, C.; Martinez, A.; Prunier, C.; Barette, C.; Soleilhac, E.; Filhol, O.; Beghin, A.; Valdameri, G.; Honoré, S.; Aci-Sèche, S.; Grierson, D.; Antonipillai, J.; Li, R.; Di Pietro, A.; Dumontet, C.; Braguer, D.; Florent, J.C.; Knapp, S.; Bernard, O.; Lafanechère, L. Pharmacological inhibition of LIM kinase stabilizes microtubules and inhibits neoplastic growth. Cancer Res., 2012, 72(17), 4429-4439.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-3342] [PMID: 22761334]
[23]
Ohashi, K.; Sampei, K.; Nakagawa, M.; Uchiumi, N.; Amanuma, T.; Aiba, S.; Oikawa, M.; Mizuno, K. Damnacanthal, an effective inhibitor of LIM-kinase, inhibits cell migration and invasion. Mol. Biol. Cell, 2014, 25(6), 828-840.
[http://dx.doi.org/10.1091/mbc.e13-09-0540] [PMID: 24478456]

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