Genautica

Janusz Sowadski

Dr. Janusz M. Sowadski at the University of California, San Diego discovered a three dimensional structure of cAMP-dependent protein kinase. The crystal structure of the catalytic subunit of this protein kinase provided a structural paradigm for the entire kinome. This critical discovery proved especially significant because the family of 518 human kinases is a key regulator of communication within the cell as well as between cells and their environment. The family is also a major oncogenic family, and mutations within any member of this family can lead to a myriad of human cancers. As Prof. E. Krebs (Nobel 1992) states in Science: "This discovery is a monumental piece of work." Dr. Sowadski' s research resulted in winning the prestigious US Supercomputing Award and in the publication of over fifty journal articles, including in Science.

In collaboration with Ciba-Gigey, now Novartis AG Basel, a group of Ciba-Gigey scientists that included J.M. Sowadski used the crystal structure of the catalytic subunit of cAMP-dependent protein kinase as a template for designing Ciba-specific inhibitors of protein kinases, most notably Novartis Gleevec®, for treatment of chronic myelogenous leukaemia (CML).

Subsequently, Dr. Sowadski co-founded, together with Dr. N. Lydon, Kinetix Pharmaceuticals, Inc., which specializes in the discovery of small molecule drugs in the field of protein kinase inhibition. After Kinetix was acquired by Amgen in 2000, Dr. Sowadski co-founded, together with Drs. K. Lu and W. Gilbert (Nobel 1980), Pintex Pharmaceuticals, this time focusing on cancer diagnostic and cancer therapeutic platforms based on phosphate specific proline isomerase Pin1. Diverse patent estates of this Company were sold to Vernalis PLC, Cambridgeshire, UK in 2005.

Presently, there are ten approved drug-inhibitors of protein kinases with a total sale of over $4 billion in 2007. In addition, eleven kinase inhibitors are in Phase III, and 130 inhibitors of protein kinases are in Phase I and II. To further increase the efficacy of kinase inhibitors, Dr. Sowadski and Dr. T. Wheeler are currently developing technologies and strategies to target cancer patients in regards to kinase inhibitor clinical trials and subsequent therapies.

Janusz M. Sowadski received a Ph.D. in Physical Chemistry from Warsaw University (Poland), and an M.S. in Biophysics from the University of Virginia. He did his postgraduate work at Yale University. His research faculty positions in various Departments of Medicine include positions at the University of California, San Diego and at Tufts University. Dr. Sowadski was the Vice President of Discovery at Kinetix Pharmaceuticals, Inc. and Chief Executive Officer and Chief Scientific Officer at Pintex Pharmaceuticals, Inc. He lives with his family in Boston.

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References:

Szymanski, A., Sowadski, J.M. Benzene polymerization in the low pressure high frequency discharge. Ann. Soc. Chim. Polonorum (Polish Academy of Sciences) 48:1115-1117, 1974.

Szymanski, A., Sowadski, J.M. Uber die Zersetzung des Methans durch Hochfrequenzentladung unter geringem druck und in statischen bedingungen. Z. Phys. Chemie, Leipzig 256:299-304, 1975.

Sowadski, J.M., Cornick, G., Kretsinger, R. Terbium replacement of calcium in parvalbumin. J. Mol. Biol. 124:123-132, 1978.

Sowadski, J.M., Foster, B.A., Wyckoff, H.W. Structure of alkaline phosphatase with zinc/magnesium, cobalt, or cadmium in the functional metal sites. J. Mol. Biol. 150:245-272, 1981.

Sowadski, J.M., Handschumacher, M.D., Murthy, H.M.K., Wyckoff, H.W. Crystallographic observations of the metal ion triple in the active site region of alkaline phosphatase. J. Mol. Biol. 170:575-581, 1983.

Wyckoff, H.W., Handschumacher, M.D., Murthy, H.M.K., Sowadski, J.M. The three dimensional structure of alkaline phosphatase from E. Coli. Advances in Enzymology and Related Areas of Molecular Biology. (ed. A. Meister). John Wiley & Sons, Inc. pp. 453-479, 1983.

Sowadski, J.M., Handschumacher, M.D., Murthy, H.M.K., Foster, B.A., Wyckoff, H.W. Refined structure of alkaline phosphatase from E. Coli at 2.8Å resolution. J.Mol. Biol. 186:417-433, 1985.

Sowadski, J.M., Xuong, N-H, Anderson, D., Taylor, S.S. Crystallization studies of cAMP-dependent protein kinase crystals of catalytic subunit diffract to 3.5Å resolution. J. Mol. Biol. 182:617-620, 1985.

Taylor, S.S., Bubis, J., Sowadski, J.M., Toner, J., Saraswat, L.D. Relation between structure and function in cAMP-dependent protein kinases. Enzyme Dynamics and Regulation, pp.327-341, 1986.

Taylor, S.S., Bubis, J., Webb, J.T., Saraswat, L.D., First, E.A., Buechler, J.A., Knighton, D., Sowadski, J.M. cAMP-dependent protein kinase: Prototype for a family of enzymes. FASEB Journal 26:2677-2685, 1988.

Tsonis, P.A., Sowadski, J.M., Goetinck, P.F. A consensus sequence in the N-terminus of exported proteins: Resemblance with metal binding domains and implications in protein translocation across membranes. Biochem. Biophys. Res. Comm. 156:99-107, 1988.

Taylor, S.S., Buechler, J.A., Slice, L.W., Knighton, D.R., Durgerian, S., Ringheim, G.E., Neitzel, J.J. Yonemoto, W.M., Sowadski, J.M., Dospmann, W. cAMP-dependent protein kinase: A framework for a diverse family of enzymes. Cold Spring Harbor Symp. Quant. Biol. 53:121-130, 1988.

Narisawa, S., Sowadski, J.M., Millan, J.L. An active site mutant of human placental alkaline phosphatase with deficient enzymatic activity and preserved immunoreactivity. Clin. Chim. Acta 186:189-196, 1989.

Carpenter, C.D., Ingraham, H.A., Cochet, C., Walton, G.M., Lazar, C.S., Sowadski, J.M., Rosenfeld, M.G., Gill, G.N. Structural analysis of the transmembrance domain of the epidermal growth factor receptor. J. Biol. Chem. 266:5750-5755, 1991.

Knighton, D.R., Zheng, J., Ten Eyck, L.F., Ashford, V.A., Xuong, N-H, Taylor, S.S., Sowadski, J.M. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253:407-414, 1991.

Knighton, D.R., Zheng, J-H., Ten Eyck, L.F., Xuong, N-H, Taylor, S.S., Sowadski, J.M. Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253:414-420, 1991.

Knighton, D.R., Xuong, N-H, Taylor, S.S., Sowadski, J.M. Crystallization studies of camp-dependent protein kinase. Co-crystals of the catalytic subunit with a 20-amino acid residue peptide inhibitor and MgATP diffract to a 3.0Å resolution. J. Mol. Biol. 220:217-220, 1991.

Zheng, J-H., Knighton, D.R., Parello, J., Taylor, S.S., Sowadski, J.M. Crystallization of catalytic subunit of adenosine cyclic monophosphate-dependent protein kinase. In: Methods in Enzymology, Vol. 200, July, 1991, (ed. T. Hunter), Academic Press, pp.508-521.

Mandecki, W., Shallcross, M.A., Sowadski, J.M., Tomazic-Allen, S. Mutagenesis of conserved residues within the active site of Escherichia coli alkaline phosphatase yields enzymes with increased kcat. Prot. Eng., 4:No.7, 801-804, 1991.

Taylor, S.S., Knighton, D.R., Zheng, J-H., Ten Eyck, L.F., Sowadski, J.M. cAMP-dependent protein kinase and the protein kinase family. Faraday Discussions, 93:143-152, 1992.

Zheng, J-H., Knighton, D.R., Xuong, N.H., Parello, J., Taylor, S.S., Sowadski, J.M. Crystallization studies of the catalytic subunit of cAMP-dependent protein kinase: Crystals of murine recombinant catalytic subunit and a mutant, Cys 343-Ser, diffract to 2.7Å resolution. Acta Crystl, B48:241-244, 1992.

Gibbs, C.S., Knighton, D.R., Sowadski, J.M., Taylor, S.S., Zoller, M.J. Systematic mutational analysis of cAMP-dependent protein kinase identifies unregulated catalytic subunits and defines regions important for the recognition of the regulatory subunit. J. Biol. Chem. 267:4806:4814, 1992.

Chen, L., Neidhart, D., Park, C., Kohlbrenner, W.M., Mandecki, W., Sowadski, J.M., Abad-Zapatero, C. Three-dimensional structure of a mutant (ASP-101>Ser) of E. Coli alkaline phosphatase with higher catalytic activity. Prot. Eng. 5:No.7, 1992.

Taylor, S.S., Knighton, D.R., Zheng, J., Ten Eyck, L.F., Sowadski, J.M. Structural framework for the protein kinase family. Ann. Rev. Cell. Biol. 8:429-462, 1992.

Knighton, D.R., Pearson, R.B., Sowadski, J.M., Means, A.R., Ten Eyck, L.F., Taylor, S.S., Sowadski, J.M. Structural basis of the intrasteric regulation of myosin light chain kinase. Science 258:130-135, 1992.

Zheng, J-H., Knighton, D.R., Ten Eyck, L.F., Karlsson, R., Xuong, N-H., Taylor, S.S., Sowadski, J.M. Structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MgATP and peptide inhibitor. Biochemistry 32:2154-2161, 1993.

Knighton,D.R., Cadena, D.L., Zheng, J-H, Ten Eyck, L.F., Taylor, S.S., Sowadski, J.M., Gill, G. Structural features that specify tyrosine kinase activity deduced from homology modeling of the EGF receptor. Proc. Natl. Acad. Sci., 90:5001-5005, 1993.

Taylor, S.S., Knighton, D.R., Zheng, J., Sowadski, J.M., Gibbs, C.S., Zoller, M.J. A template for the protein kinase family. TIBS Review 18(3):84-89, March, 1993.

Grzybowski, J. and Sowadski, J.M. Kinazy bialkowe i ich inhibitor. Nowa szansa dla onkologii? (Protein kinases and their inhibitors – a new chance for oncology?) Oncogenes, (Nowotwory), 43:68-76, 1993.

Knighton,D.R., Bell, S., Zheng, J., Ten Eyck, L.F., Xuong, N-H, Taylor, S.S., Sowadski, J.M. 2.0Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinases complexed with a peptide inhibitor and detergent. Acta Cryst., (Fast communication), D49:357-361, 1993.

Zheng, J-H, Trafny, E.A., Knighton, D.R., Xuong, N-H., Taylor, S.S., Ten Eyck, L.F., Sowadski, J.M. 2.2Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor. Acta Cryst., D49:362-365, 1993.

Karlsson, R., Zheng, J., Xuong, N-H, Taylor, S.S., and Sowadski, J.M. Crystal structure of the mammalian catalytic subunit of cAMP-dependent protein kinase and an inhibitor peptide displays an open conformation. Acta Cryst., D49:381-388, 1993.

Taylor, S.S., Zheng, J-H., Radzio-Andzelm, E., Knighton, D.R., Ten Eyck, L.F., Sowadski, J.M., Herzberg, F.W. and Yonemoto, W.M. cAMP-dependent protein kinase defines family of enzymes. Phil. Tran., Royal Society London, B340:315-324, 1993.

Zheng, J-H., Knighton, D.R., Xuong, N.H., Taylor, S.S., Sowadski, J.M., Ten Eyck, L.F. Crystal structures of the myristylated catalytic subunit of cAMP-dependent proteinn kinase reveal open and closed conformations. Protein Science, 2:1559-1573, 1993.

Marcote, M.J., Knighton, D.R., Basi, G., Sowadski, J.M., Brambilla, P., Draetta, G., and Taylor, S.S. A three-dimensional model of the cdc2 protein kinase of cyclin- and suc1-binding regions and phosphorylation sites. Molecular and Cellular Biology, 13:5122-5133, 1993.

Taylor, S.S., Radzio-Anzelm, E., Knighton, D.R., Ten Eyck, L.F., Sowadski, J.M., Herzberg, F.W., Yonemoto, W., and Zheng, J. Crystal structures of the catalytic subunit of cAMP-dependent protein kinase reveal general features of the protein kinase family. Receptor 3:3, 165-172, 1993.

Gallagher, P.J., Herring, B.P., Trafny, A., Sowadski, J.M., and Stull, J. T. A molecular mechanism for autoinhibition of myosin light chain kinases. J. Biol. Chem. 268:26578-26582, 1993.

Madhusudan, Trafny, E.A., Xuong, N-H, Adams, J.A., Ten Eyck, L.F., Taylor, S.S., and Sowadski, J.M. cAMP-dependent protein kinase: Crystallographic insights into substrate recognition and phosphotransfer. Protein Science, 3:176-187, 1994.

Karlsson, R.F., Madhusudan, Taylor, S.S., Sowadski, J.M. Intermolecular contacts in various crystal forms related to the open and closed conformational states of the catalytic subunit of cAMP-dependent protein kinase. Acta Cryst., Sec.D, 50:657-662, 1994.

Vihinen, M., Vetrie, D., Maniar, H.S., Ochs, H.D., Zhu, Q., Vorechovsky, I., Webster, A.D.B., Notarangelo, L.D., Nilsson, L., Sowadski, J.M., Smith, E. Structural basis for X-linked agammaglobulinemia. Proc. Natl. Acad. Sci., 91:12803-12807, 1994.

Sowadski, J.M. Crystallization of Membrane Proteins. Current Opinion in Structural Biology, 4:761-764, 1994. Senften, M., Schenker, G., Sowadski, J.M., Ballmer-Hofer, K. Catalytic activity and transformation potential of v-Src require arginine 385 in the substrate binding pocket. Oncogene, 10:199-203, 1995.

Furet, P., Caravetti, G., Lydon, N., Priestle, J.P., Sowadski, J.M., Trinks, U., Traxler, P. Modelling study of protein kinase inhibitors: binding mode of staurosporine origin of the selectivity of CGP 52411. J. Computer-Aided Molecular Design, 9:465-472, 1995.

Sowadski, J.M. Crystallization of membrane proteins—in need of a new focus. Journal of Bioenergetics and Biomembranes, 28:7-12, 1996.

Sowadski, J.M., Ellis, C., and Madhusudan. Detergent binding to unmyristylated protein kinase A – structural implications for the role of myristate. J. Bioenergetics and Biomembranes, 28:7-12, 1996.

Sowadski, J.M., Ellis C.A., Karlsson, R., and Madhusudan. Design of ATP competitive specific inhibitors of protein kinases using template modeling. Structure based drug design: Diseases, targets, techniques, and developments-Volume I. (Ed. Pandi Veerapandian & Publisher, Marcel Dekker, Inc.), 1997.

Ginalski, K., Lesyng, B., Sowadski, J.M., and Wojciechowski, M. Modeling of active forms of protein kinases: p38 – A case study. Acta Biochimica Polonica, 44:557-564, 1997.

Joukov, V., Vihinen, M., Vainikka, S., Sowadski, J.M., Alitalo, K. and Bergman, M. Identification of Csk tyrosine phosphorylation site and a tyrosine residue important for kinase domain structure. Biochem. J.., 322:927-935, 1997. Sowadski, J.M., Epstein, L.F., Lankiewicz, L., and Karlsson, R. Conformational diversity of catalytic cores of protein kinases. Pharmacology & Therapeutics. Vol. 82, Nos. 2-3, pp. 157-164, 1999.

Sowadski, J.M., Epstein, L.F. Protein Kinases. Encyclopedia of Life Sciences Macmillan London, Nature Publishing Group 2000.

Ayala, G., Wang, D., Wulf, G., Frolov, A., Le, R., Sowadski, J. M., Wheeler, T., Lu, K., and Bao, L. The Prolyl Isomerase Pin1 is a Novel Prognostic Marker in Human Prostate Cancer. Cancer Research 63, 6244-6251, 2003.