Matthias Wymann

Biographical sketch:

Matthias P. Wymann (MPW) studied Biochemistry at the Swiss Federal Institute of Technology [ETH] in Zurich. In 1988 he concluded his Ph.D. at the Theodor Kocher Institute in Bern, where he investigated signal transduction in granulocytes with Prof. Marco Baggiolini. After a post-doc in Linköping with Prof. Karl-Eric Magnusson he started as independent principal investigator at the University of Fribourg in 1991. Here he discovered wortmannin as the first phosphoinositide 3-kinase (PI3K) inhibitor, and elucidated inhibitor-PI3K interactions. In 2004 MPW moved to the University of Basel, where he leads the “Cancer & Immunobiology” group at the Department of Biomedicine.

MPW’s research elucidates the molecular function and physiologic importance of PI3Ks. In chronic inflammation and allergy PI3Kγ relays signals emerging from G protein-coupled receptors (GPCRs) to cell migration and mast cell degranulation. PI3Kγ knock-in strategies illustrated that PI3Kγ acts as a scaffold protein, which modulates cardiac contractility and development of obesity and diabetes. MPW has also promoted efforts to develop PI3Kγ-specific, bioavailable inhibitors, which demonstrated the feasibility to target PI3Kγ in chronic inflammation and allergy, e.g. rheumatoid arthritis and atherosclerosis. Current research concentrates on the role of PI3K and PI3K-related kinases in cancer and inflammation, as well as the development of chemical biological tools to improve spacial and temporal resolution in phosphoinositide signaling. Translational development of PI3K and mTOR kinase inhibitors at UniBas culminated in the pan-PI3K/mTOR inhibitor PQR309 (bimiralisib), which made it to phase II clinical studies and is explored in solid tumors and topical applications. Latest developments include covalent inhibitors specifically targeting PI3Kγ in cancer.

Project relevant publications:

Bissegger L, Constantin TA, Keles E, Raguž L, Barlow-Busch I, Orbegozo C, Schaefer T, Borlandelli V, Bohnacker T, Sriramaratnam R, Schäfer A, Gstaiger M, Burke JE, Borsari C, Wymann MP. (2024) Rapid, potent, and persistent covalent chemical probes to deconvolute PI3Kγ signaling. Chem Sci 15:20274-20291.

Lanahan SM, Yang L, Jones KM, Qi Z, Cabrera EC, Cominsky LY, Ramaswamy A, Barmada A, Gabernet G, Uthaya Kumar DB, Xu L, Shan P, Wymann MP, Kleinstein SH, Rao VK, Mustillo P, Romberg N, Abraham RS, Lucas CL. (2024) PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells. Nat Immunol 25:1422-1431.

Koumantou D, Adiko AC, Bourdely P, Nugue M, Boedec E, El-Benna J, Monteiro R, Saveanu C, Laffargue M, Wymann MP, Dalod M, Guermonprez P, Saveanu L. (2024) Specific Requirement of the p84/p110 Complex of PI3Kγ for Antibody-Activated, Inducible Cross-Presentation in Murine Type 2 DCs. Adv Sci (Weinh) e2401179.

Jauslin WT, Schild M, Schaefer T, Borsari C, Orbegozo C, Bissegger L, Zhanybekova S, Ritz D, Schmidt A, *Wymann M, *Gillingham D. (2024) A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kγ. Chemical Science 15:683-691. *Corresponding authors.

De Pascale M, Bissegger L, Tarantelli C, Beaufils F, Prescimone A, Mohamed Seid Hedad H, Kayali O, Orbegozo C, Raguž L, Schaefer T, Hebeisen P, Bertoni F, *Wymann MP, *Borsari C. (2023) Investigation of morpholine isosters for the development of a potent, selective and metabolically stable mTOR kinase inhibitor. Eur J Med Chem 248:115038. *Corresponding authors.

Borsari C, Keles E, McPhail JA, Schaefer A, Sriramaratnam R, Goch W, Schaefer T, De Pascale M, Bal W, Gstaiger M, Burke JE, Wymann MP. (2022) Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kγ. J Am Chem Soc 144:6326-6342.

Lanahan SM, Wymann MP, Lucas CL. (2022) The role of PI3Kγ in the immune system: new insights and translational implications. Nat Rev Immunol 22:687-700.

Borsari C, Wymann MP. (2021) Targeting Phosphoinositide 3-Kinase – Five Decades of Chemical Space Exploration. Chimia (Aarau) 75:1037-1044.

Rathinaswamy MK, Gaieb Z, Fleming KD, Borsari C, Harris NJ, Moeller BE, Wymann MP, Amaro RE, Burke JE. (2021) Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors. Elife 10:e64691.

Borsari C, De Pascale M, Wymann MP. (2021) Chemical and Structural Strategies to Selectively Target mTOR Kinase. ChemMedChem 16:2744-2759.

Borsari C, Keles E, Rageot D, Treyer A, Bohnacker T, Bissegger L, De Pascale M, Melone A, Sriramaratnam R, Beaufils F, Hamburger M, Hebeisen P, Löscher W, Fabbro D, Hillmann P, Wymann MP. (2020) 4-(Difluoromethyl)-5-(4-((3R,5S)-3,5-dimethylmorpholino)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)pyridin-2-amine (PQR626), a Potent, Orally Available, and Brain-Penetrant mTOR Inhibitor for the Treatment of Neurological Disorders. J Med Chem 63:13595-13617.