Summary

Scott Larsen spent over 22 years in the pharmaceutical industry (The Upjohn Co, Pharmacia, Pfizer) as a synthetic medicinal chemist, rising to the rank of Associate Director and Fellow, before joining UM in 2007.  He is currently Director of the Vahlteich Medicinal Chemistry Core (VMCC), the mission of which is to assist UM colleagues in the development of biologically active small molecules, usually identified by high throughput screening (HTS).  This entails the design and synthesis of new analogs to improve potency and selectivity, and the refinement of physicochemical properties necessary for good cellular and in vivo activity (including solubility, permeability and metabolic stability).

Dr. Larsen received Pharmacia & Upjohn Special Recognition Awards in 1998 and 2000, was a charter member of the Pharmacia Fellows in 2001, received a Pfizer Achievement Award in 2007 and was named the Joseph Burckhalter Collegiate Professor of Medicinal Chemistry in 2014.  He is a member of the Medicinal Chemistry Division of the American Chemical Society and has served on NIH Special Emphasis Panels for NIDA and NCATS.

The Larsen lab is currently engaged in five major projects (collaborators in parentheses):

1) Inhibitors of Rho/MRTF/SRF-mediated gene transcription for the treatment of metastatic cancer and fibrosis. (Richard Neubig (MSU), Dinesh Khanna)

2) Improving the CNS-permeability of a glycosphingolipid biosynthesis inhibitor for the treatment of CNS-based lipidoses, which can cause rare but devastating diseases such as Tay-Sachs and Gaucher. (James Shayman, Richard Keep)

3) Novel probes for investigating mechanisms of Mycobacterium tuberculosis pH-driven adaptation  (Rob Abramovitch (MSU))

4) Structure-based design of Isozyme-selective inhibitors of ALDH for treating chemoresistant ovarian cancer (Ron Buckanovich (U Pitt), Nouri Neamati, Thomas Hurley (IUPUI))

5) CNS-permeable inhibitors of Toxoplasma gondii Cathepsin L for treatment of toxoplasmosis (Vern Carruthers)

 

Dr. Larsen is no longer taking new graduate students.

Research Interests

  • Development of small molecule hits from high throughput screening to in vivo proof-of-concept studies

  • Use of photoaffinity probes for identification of the molecular targets of small molecules from phenotypic HTS

Awards

  • 2014 UM Collegiate Research Professor Award, Univ of Michigan

Selected Publications

  • Huddle, B.C.; Buchman, C.D.; Chtcherbinine, M.; Grimley, E.; Debnath, B.; Mehta, P.; Yang, K.; Morgan, C.A.; Li, S.; Felton, J.; Sun, D.; Mehta, G.; Neamati, N.; Buckanovich, R.J. Hurley, T.D.; Larsen, S.D. “Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy”, J. Med. Chem.2018, 61, 8754-73.

     

    Waldschmidt, H.V.; Bouley, R.; Kirchhoff, P.D.; Lee, P.H.; Tesmer, J.J.G.; Larsen, S.D. “Utilizing a Structure-Based Docking Approach to Develop Potent  G Protein-Coupled Receptor Kinase (GRK) 2 and 5 Inhibitors”, Bioorg. Med. Chem. Lett. 2018, 28, 1507-15

     

    Zwicker, J.D.; Diaz, N.A.; Guerra, A.J.; Kirchhoff, P.D.; Wen, B.; Sun, D.; Carruthers, V.B.; Larsen, S.D. “Optimization of Dipeptidic Inhibitors of Cathepsin L for Toxoplasma gondii Selectivity and CNS Permeability”, Bioorg. Med. Chem. Lett.  2018, 28, 1972-80.

     

    Waldschmidt, H.V.; Homan, K.T.; Cato, M.C.; Cruz-Rodriguez, O.; Cannavo, A.; Wilson, M.W.; Song, J.; Cheung, J.Y.; Koch, W.J.; Tesmer, J.J.G.; Larsen, S.D. “Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine”, J. Med. Chem 2017, 60, 3052-69.

     

    Hutchings, K.M.; Lisabeth, E.M.; Rajeswaran, W.; Wilson, M.W.; Sorenson, R.J.; Campbell, P.L.; Ruth, J.H.; Amin, A.; Tsou, P.-S.; Leipprandt, J.R.; Olson, S.R.; Wen, B.; Zhao, T.; Sun, D.; Khanna, D.; Fox, D.A.; Neubig, R.R.; Larsen, S.D. “Pharmacokinetic Optimization of CCG-203971: Novel Inhibitors of the Rho/MRTF/SRF Transcriptional Pathway as Potential Antifibrotic Therapeutics for Systemic Scleroderma”, Bioorg. Med. Chem. Lett.  2017, 27, 1744-49.

     

    Waldschmidt, H.; Homan, K.; Cruz-Rodriguez, O.; Cato, M.; Waninger-Saroni, J.; Larimore, K.; Cannavo, A.; Song, J.; Cheung, J.; Koch, W.; Tesmer, J.; Larsen, S.D. “Structure-Based Design, Synthesis and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors”, J. Med. Chem. 2016, 59, 3793-3807.

     

    Zheng, H.; Colvin, C.J.; Johnson, B.K.; Kirchhoff, P.; Wilson, M.; Jorgensen-Muga, K.; Larsen, S.D.; Abramovitch, R.B. “Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence”, Nat. Chem. Biol. 2016, 13, 218-25

     

    Haak, A.; Tsou, P.-S.; Amin, M.A.; Ruth, J.H.; Campbell, P.; Fox, D.A.; Khanna, D.; Larsen, S.D.; Neubig, R.R. “Targeting the myofibroblast genetic switch: inhibitors of MRTF/SRF-regulated gene transcription prevent fibrosis in a murine model of skin injury”, J. Pharmacol. Exp. Ther. 2014, 349, 480-86.

     

    Shayman, J.A.; Larsen, S.D. “The Development and Use of Small Molecule Inhibitors of Glycosphingolipid Metabolism for the Treatment of Lysosomal Storage Disease”, J. Lipid Res. 2014, 55, 1215-25.

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