Matthias P. Wymann

Institution: Department of Biomedicine

Address:

University of Basel Mattenstrasse 28 4058 Basel

Email: Matthias.Wymann@UniBas.CH

Group website: biomedizin.unibas.ch/wymann

Phone: +41 61 207 5046

Research interests:

Wymann has introduced the first PI3K inhibitor, wortmannin (Arcaro and Wymann 1993), and elucidated inhibitor PI3K-interactions biochemically (Wymann et al. 1996) and in 3D with R. Williams (Walker et al. 2000). The main focus of his research in the past years was the investigation of the molecular function and physiologic importance of PI3K in chronic inflammation, allergy and cancer. In collaboration with E. Hirsch it was established that PI3Kg relays signals emerging from G protein-coupled receptors (GPCRs), and that other class I PI3Ks do not participate in chemokine-induced PtdIns(3,4,5)P3 production (Hirsch et al., 2000). Later, it was shown that activation of mast cells by antigen/IgE depends on PI3Kg in vivo. This was surprising at the time, but provided an important step towards the characterization of PI3Kg as a drug target in allergy (Laffargue et al., 2002). Based on previous structure/function investigations (Bondeva et al., 1998; Walker et al., 2000), various strategies for PI3Kg knock-in strategies were designed. Recently, these studies have led to the insight, that PI3Kg is required for the down-regulation of cardiac cAMP, and thus affects the contractile response of cardiomyocytes (Patrucco et al., 2004; Perino et al. 2011). Wymann has also contributed to the development of PI3Kg–specific, bioavailable inhibitors, which demonstrated the feasibility to target PI3Kg in chronic inflammation (Camps et al. 2005; see EU FP5, ACID project; FP6, MAIN). In 2009, Wymann has initiated an ESF-funded consortium (TraPPs) to develop advanced tools to track and modulate phosphoinositide signaling (Bohnacker et al. 2009; Erhart et al. 2013; Zimmermann et al. 2014). A role for PI3Kg in the control of thermogenesis was established (Becattini et al. 2011); and a novel Ca2+/protein kinase Cb-dependent mechanisms of PI3K activation was discovered in mast cells recently (Collmann et al. 2013; Walser et al. 2013). Wymann is a founder of PIQUR Therapeutics AG Basel; the pan-PI3K inhibitor PQR309 is now in phase II clinical trials in solid tumors and lymphoma (Bohnacker et al. 2017; Beaufils et al. 2017).

Selected publications:

111. Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP. 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology. J Med Chem 2017; 60, 7524- 110. Breasson L, Becattini B, Sardi C, Molinaro A, Zani F, Marone R, Botindari F, Bousquenaud M, Ruegg C, Wymann MP*, Solinas G.* PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity. Sci Signal 2017; 10, aaf2969. *corresponding authors. 109. Bohnacker T, Prota AE, Beaufils F, Burke JE, Melone A, Inglis AJ, Rageot D, Sele AM, Cmiljanovic V, Cmiljanovic N, Bargsten K, Aher A, Akhmanova A, Díaz JF, Fabbro D, Zvelebil M, Williams RL, Steinmetz MO, Wymann MP. Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention. Nat Commun 2017; 8, 14683. 103. Walser R, Burke JE, Gogvadze E, Bohnacker T, Zhang X, Hess D, Kuenzi P, Leitges M, Hirsch E, Williams RL, Laffargue M, Wymann MP (2013) PKCbeta Phosphorylates PI3Kgamma to Activate It and Release It from GPCR Control. PLoS Biol. 11:e1001587. 101. Collmann E, Bohnacker T, Marone R, Dawson , Rehberg M, Stringer R, Krombach F, Burkhart C, Hirsch E, Hollingworth JG, Thomas M, Wymann MP (2013) Transient Targeting of PI3K Acts as a Roadblock in Mast Cells' Route to Allergy. J. Allergy Clin. Immunol. 132:959-. 81. Bohnacker T, Marone R, Collmann E, Calvez R, Hirsch E, Wymann MP (2009) PI3Kg Adapter Subunits Define Coupling to Degranulation and Cell Motility by Distinct PtdIns(3,4,5)P3 Pools in Mast Cells. Sci. Signal., 2(74):ra27. 75. Wymann MP, Schneiter R (2008) Lipid signalling in disease. Nat. Rev. Mol. Cell Biol., 9:162-.

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