The Hedgehog (Hh) signaling pathway is crucial for vertebrate embryonic development, tissue homeostasis and regeneration. Hh signaling is upregulated in basal cell carcinoma and medulloblastoma and Hh pathway inhibitors targeting the Smoothened (SMO) protein are in clinical use. However, the signaling cascade is incompletely understood and novel druggable proteins in the pathway are in high demand. We describe the discovery of the Hh-pathway modulator Pipinib by means of cell-based screening. Target identification and validation revealed that Pipinib selectively inhibits phosphatidylinositol 4-kinase IIIβ (PI4KB) and suppresses GLI-mediated transcription and Hh target gene expression by impairing SMO translocation to the cilium. Therefore, inhibition of PI4KB and, consequently, reduction in phosphatidyl-4-phosphate levels may be considered an alternative approach to inhibit SMO function and thus, Hedgehog signaling.

Current address Department of Chemistry The Scripps Research Institute 110 Scripps Way Jupiter FL 33458 USA

Department of Cell and Developmental Biology Max Planck Institute for Molecular Biomedicine Röntgenstr 20 48149 Münster Germany

Department of Cell Biology Johns Hopkins University School of Medicine 855 N Wolfe Street 453 Rangos Baltimore MD 21205 USA

Department of Chemical Biology Max Planck Institute of Molecular Physiology Otto Hahn Straße 11 44227 Dortmund Germany

Faculty of Chemistry and Chemical Biology Technical University Dortmund Otto Hahn Straße 6 44221 Dortmund Germany

Institute of Organic Chemistry and Biochemistry Flemingovo nam 2 16610 Prague 6 Czech Republic

Lead Discovery Center GmbH Otto Hahn Straße 15 44227 Dortmund Germany

Medical Faculty University of Münster Domagkstr 3 48149 Münster Germany

Technische Universität Dresden DFG Research Center for Regenerative Therapies Dresden 01307 Dresden Germany

Zobrazit více v PubMed

Wu F., Zhang Y., Sun B., McMahon A. P., Wang Y., Cell Chem. Biol. 2017, 24, 252. PubMed PMC

Hui C.-C., Angers S., Annu. Rev. Cell Dev. Biol. 2011, 27, 513; PubMed

Katoh Y., Katoh M., Curr. Mol. Med. 2009, 9, 873. PubMed

Xie J., Murone M., Luoh S. M., Ryan A., Gu Q., Zhang C., Bonifas J. M., Lam C. W., Hynes M., Goddard A., Rosenthal A., Epstein E. H., Sauvage F. J. d., Nature 1998, 391, 90. PubMed

Raffel C., Jenkins R. B., Frederick L., Hebrink D., Alderete B., Fults D. W., James C. D., Cancer Res. 1997, 57, 842. PubMed

Abou-Alfa G. K., Lewis L. D., LoRusso P., Maitland M., Chandra P., Cheeti S., Colburn D., Williams S., Simmons B., Graham R. A., Cancer Chemother. Pharmacol. 2017, 80, 29; PubMed PMC

Dummer R., Guminski A., Gutzmer R., Dirix L., Lewis K. D., Combemale P., Herd R. M., Kaatz M., Loquai C., Stratigos A. J., Schulze H.-J., Plummer R., Gogov S., Pallaud C., Yi T., Mone M., Chang A. L. S., Cornélis F., Kudchadkar R., Trefzer U., Lear J. T., Sellami D., Migden M. R., J. Am. Acad. Dermatol. 2016, 75, 113; PubMed

Minami Y., Minami H., Miyamoto T., Yoshimoto G., Kobayashi Y., Munakata W., Onishi Y., Kobayashi M., Ikuta M., Chan G., Woolfson A., Ono C., Shaik M. N., Fujii Y., Zheng X., Naoe T., Cancer Sci. 2017, 108, 1628. PubMed PMC

Yauch R. L., Dijkgraaf G. J. P., Alicke B., Januario T., Ahn C. P., Holcomb T., Pujara K., Stinson J., Callahan C. A., Tang T., Bazan J. F., Kan Z., Seshagiri S., Hann C. L., Gould S. E., Low J. A., Rudin C. M., Sauvage F. J. d., Science 2009, 326, 572; PubMed PMC

Peukert S., Miller-Moslin K., ChemMedChem 2010, 5, 500; PubMed

Sharpe H. J., Wang W., Hannoush R. N., de Sauvage F. J., Nat. Chem. Biol. 2015, 11, 246; PubMed

Owens A. E., et al., J. Am. Chem. Soc. 2017, 139, 12559. PubMed PMC

Teglund S., Toftgard R., Bba-Rev. Cancer 2010, 1805, 181. PubMed

Bao R., Lai C., Qian C., Patent US20130102595; Curis, Inc., United States, 2013.

González Cabrera D., Le Manach C., Douelle F., Younis Y., Feng T. S., Paquet T., Nchinda A. T., Street L. J., Taylor D., de Kock C., Wiesner L., Duffy S., White K. L., Zabiulla K. M., Sambandan Y., Bashyam S., Waterson D., Witty M. J., Charman S. A., Avery V. M., Wittlin S., Chibale K., J. Med. Chem. 2014, 57, 1014; PubMed

Li X. Y., Zhang Y. M., Tang J., Yang F., Nan F. J., Chin. J. Chem. 2010, 28, 1437.

Kremer L., Schultz-Fademrecht C., Baumann M., Habenberger P., Choidas A., Klebl B., Kordes S., Scholer H. R., Sterneckert J., Ziegler S., Schneider G., Waldmann H., Angew. Chem. Int. Ed. 2017, 56, 13021; PubMed

Angew. Chem. 2017, 129, 13201.

Wu X., Walker J., Zhang J., Ding S., Schultz P. G., Chem. Biol. 2004, 11, 1229. PubMed

Hoch L., Faure H., Roudaut H., Schoenfelder A., Mann A., Girard N., Bihannic L., Ayrault O., Petricci E., Taddei M., Rognan D., Ruat M., FASEB J. 2015, 29, 1817; PubMed PMC

Wang Y., Arvanites A. C., Davidow L., Blanchard J., Lam K., Yoo J. W., Coy S., Rubin L. L., McMahon A. P., ACS Chem. Biol. 2012, 7, 1040; PubMed PMC

Wilson C. W., Chen M.-H., Chuang P.-T., PloS one 2009, 4, e5182. PubMed PMC

Sinha S., Chen J. K., Nat. Chem. Biol. 2006, 2, 29. PubMed

Chen J. K., Taipale J., Cooper M. K., Beachy P. A., Genes Dev. 2002, 16, 2743. PubMed PMC

Chen J. K., Taipale J., Young K. E., Maiti T., Beachy P. A., Proc. Natl. Acad. Sci. USA 2002, 99, 14071. PubMed PMC

Partridge F. A., Forman R., Willis N. J., Bataille C. J. R., Murphy E. A., Brown A. E., Heyer-Chauhan N., Marinic B., Sowood D. J. C., Wynne G. M., Else K. J., Russell A. J., Sattelle D. B., PLoS Neglected Trop. Dis. 2018, 12 (7): e00064887. PubMed PMC

Bravo-Altamirano K., George K. M., Frantz M.-C., Lavalle C. R., Tandon M., Leimgruber S., Sharlow E. R., Lazo J. S., Wang Q. J., Wipf P., ACS Med. Chem. Lett. 2011, 2, 154; PubMed PMC

S. Kaneko, T. Fujimoto, Y. Nagasawa, M. Kato, H. Kurata, Sankyo Co., Ltd., Japan, 2008, Patent JP 2006-189089; JP 2008013527 .

Stelzer G., Rosen N., Plaschkes I., Zimmerman S., Twik M., Fishilevich S., Stein T. I., Nudel R., Lieder I., Mazor Y., Kaplan S., Dahary D., Warshawsky D., Guan-Golan Y., Kohn A., Rappaport N., Safran M., Lancet D., Curr. Protoc. Bioinf. 2016, 54, 130.1–1.30.33. PubMed

Martinez Molina D., Jafari R., Ignatushchenko M., Seki T., Larsson E. A., Dan C., Sreekumar L., Cao Y., Nordlund P., Science 2013, 341, 84. PubMed

Jiang K., Liu Y., Fan J., Zhang J., Li X.-A., Evers B. M., Zhu H., Jia J., PLoS Biol. 2016, 14, e1002375. PubMed PMC

Szentpetery Z., Varnai P., Balla T., Proc. Natl. Acad. Sci. USA 2010, 107, 8225; PubMed PMC

Tan J., Brill J. A., Crit. Rev. Biochem. Mol. Biol. 2014, 49, 33. PubMed

Garcia-Gonzalo F. R., Phua S. C., Roberson E. C., Garcia G. r., Abedin M., Schurmans S., Inoue T., Reiter J. F., Dev. Cell 2015, 34, 400; PubMed PMC

Chávez M., Ena S., van Sande J., Kerchove d'Exaerde A. d., Schurmans S., Schiffmann S. N., Dev. Cell 2015, 34, 338. PubMed

Balla A., Tuymetova G., Tsiomenko A., Várnai P., Balla T., Mol. Biol. Cell 2005, 16, 1282; PubMed PMC

Dowler S., Currie R. A., Campbell D. G., Deak M., Kular G., Downes C. P., Alessi D. R., Biochem. J. 2000, 351, 19. PubMed PMC

Hammond G. R. V., Machner M. P., Balla T., J. Cell Biol. 2014, 205, 113. PubMed PMC

Komatsu T., Kukelyansky I., McCaffery J. M., Ueno T., Varela L. C., Inoue T., Nat. Methods 2010, 7, 206. PubMed PMC

Gaus G., Stieve H., Z. Naturforsch. C 1992, 47, 300. PubMed

Boura E., Nencka R., Exp. Cell Res. 2015, 337, 136. PubMed

Piperno G., LeDizet M., Chang X. J., J. Cell Biol. 1987, 104, 289. PubMed PMC

Yavari A., Nagaraj R., Owusu-Ansah E., Folick A., Ngo K., Hillman T., Call G., Rohatgi R., Scott M. P., Banerjee U., Dev. Cell 2010, 19, 54. PubMed PMC

Blomen V. A., Majek P., Jae L. T., Bigenzahn J. W., Nieuwenhuis J., Staring J., Sacco R., van Diemen F. R., Olk N., Stukalov A., Marceau C., Janssen H., Carette J. E., Bennett K. L., Colinge J., Superti-Furga G., Brummelkamp T. R., Science 2015, 350, 1092. PubMed

Mejdrová I., Chalupská D., Plačková P., Müller C., Šála M., Klíma M., Baumlová A., Hřebabecký H., Procházková E., Dejmek M., Strunin D., Weber J., Lee G., Matoušová M., Mertlíková-Kaiserová H., Ziebuhr J., Birkus G., Boura E., Nencka R., J. Med. Chem. 2017, 60, 100. PubMed

Waring M. J., Andrews D. M., Faulder P. F., Flemington V., McKelvie J. C., Maman S., Preston M., Raubo P., Robb G. R., Roberts K., Rowlinson R., Smith J. M., Swarbrick M. E., Treinies I., Winter J. J. G., Wood R. J., Chem. Commun. 2014, 50, 5388. PubMed

Corcoran R. B., Scott M. P., Proc. Natl. Acad. Sci. USA 2006, 103, 8408. PubMed PMC

Byrne E. F. X., Sircar R., Miller P. S., Hedger G., Luchetti G., Nachtergaele S., Tully M. D., Mydock-McGrane L., Covey D. F., Rambo R. P., Sansom M. S. P., Newstead S., Rohatgi R., Siebold C., Nature 2016, 535, 517; PubMed PMC

Huang P., Nedelcu D., Watanabe M., Jao C., Kim Y., Liu J., Salic A., Cell 2016, 166, 1176; PubMed PMC

Luchetti G., Sircar R., Kong J. H., Nachtergaele S., Sagner A., Byrne E. F., Covey D. F., Siebold C., Rohatgi R., eLife 2016, 5, e20304. PubMed PMC

Rana R., Carroll C. E., Lee H.-J., Bao J., Marada S., Grace C. R. R., Guibao C. D., Ogden S. K., Zheng J. J., Nat. Commun. 2013, 4, 2965. PubMed PMC

Clayton E. L., Minogue S., Waugh M. G., Prog. Lipid Res. 2013, 52, 294. PubMed PMC