Skip to main content
John Tesmer Research Group

Identification and Rational Design of Small Molecule Probes

The Tesmer lab is interested in the discovery of selective small molecule agents that can probe signaling cascades of interest in more physiological contexts or that can serve as leads for drug development. Most of the cascades described in the other research sections are either involved in cardiovascular disease or cancer, and as such these compounds would have potential applications ranging from treatment of congestive heart failure to inhibition of GPCR-linked metastasis and tumor growth.  Most of our published work thus far focuses on the GRKs, which can profoundly influence signaling through GPCRs. In 2012 the lab identified the SSRI paroxetine (Paxil) as a moderately selective GRK2 inhibitor, which was later shown to reverse heart malfunction in mice subjected to infarction (1). We have identified even more potent chemical scaffolds with distinct selectivity profiles for the various GRKs (2, 3) that are being developed in collaboration with medicinal chemists. The most recent efforts in the lab center on the development of covalent inhibitors for GRK5/6 (4).
Project 5
Publications

  1. Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, Tesmer JJG, Koch WJ. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015 Mar 4;7(277):277ra31. PMC4768806

  2. Bouley R, Waldschmidt HV, Cato MC, Cannavo A, Song J, Cheung JY, Yao X-Q, Koch WJ, Larsen SD, and Tesmer JJG: Structural determinants influencing the potency and selectivity of indazole-paroxetine hybrid G protein-coupled receptor kinase 2 inhibitors. Mol. Pharmacol. 2017, 92:707-717. PMCID: 5691592

  3. Waldschmidt HV, Homan KT, Cato MC, Cruz-Rodríguez O, Cannavo A, Wilson MW, Song J, Cheung JY, Koch WJ, Tesmer JJG, Larsen SD: Structure-based design of highly selective and potent G protein-coupled receptor kinase 2 inhibitors based on paroxetine. J. Med. Chem. 2017, 60:3052-3069. PMC5641445

  4. Rowlands RA, Chen Q, Bouley RA, Avramova LV, Tesmer JJG, White AD: Generation of highly selective, potent, and covalent G protein-coupled receptor kinase 5 inhibitors. J. Med. Chem. 2021, 64:566-585. PMC7909074