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 co-directed the Vahlteich Medicinal Chemistry Core (VMCC) from 2008-2019, 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.

Dr. Larsen no longer has an active laboratory, but continues to consult on three major projects (collaborators in parentheses):

1) Inhibitors of Rho/MRTF/SRF-mediated gene transcription for the treatment of fibrosis. (Richard Neubig (MSU))

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)

3) ALDH1A inhibitors for treating chemoresistant ovarian cancer (Ron Buckanovich (U Pitt), Nouri Neamati, Thomas Hurley (IUPUI))

 

Dr. Larsen is no longer taking new graduate students or postdocs.

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.; Grimley, E.; Chtcherbinine, M.; Buchman, C.D.; Debnath, B.; McGonigal, S.C.; Mao, S.; Li, S.; Felton, J.; Pan, S.; Wen, B.; Sun, D.; Neamati, N.; Buckanovich, R.J.; Hurley, T.D.; Larsen, S.D. “Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of Aldehyde Dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy”, Eur. J. Med. Chem. 2021, 211, 113060. https://pubmed.ncbi.nlm.nih.gov/33341649/

     

    Wilson, M.W.; Shu, L.; Hinkovska-Galcheva, V.; Jin, Y.; Rajeswaran, W.; Abe, A.; Zhao, T.; Luo, R.; Wang, L.; Wen, B.; Liou, B.; Fannin, V.; Sun, D.; Sun, Y.; Shayman, J.A.; Larsen, S.D. “Optimization of Eliglustat-based Glucosylceramide Synthase Inhibitors as Substrate Reduction Therapy for Gaucher Disease Type 3”, ACS Chem. Neuroscience 2020, 11, 3464-73.  https://pubmed.ncbi.nlm.nih.gov/33035424/

     

    Zwicker, J.D.; Smith, D.; Guerra, A.J.; Hitchens, J.R.; Haug, N.; Vander Roest, S.; Lee, P.; Wen, B.; Sun, D.; Wang, L.; Keep, R.F.; Xiang, J.; Carruthers, V.B.; Larsen, S.D. “Discovery and Optimization of Triazine Nitrile Inhibitors of Toxoplasma gondii Cathepsin L for the Treatment of Chronic Toxoplasmosis in the CNS”, ACS Chem. Neuroscience 2020, 11, 2450-63.  Zwicker, J.D.; Smith, D.; Guerra, A.J.; Hitchens, J.R.; Haug, N.; Vander Roest, S.; Lee, P.; Wen, B.; Sun, D.; Wang, L.; Keep, R.F.; Xiang, J.; Carruthers, V.B.; Larsen, S.D. “Discovery and Optimization of Triazine Nitrile Inhibitors of Toxoplasma gondii Cathepsin L for the Treatment of Chronic Toxoplasmosis in the CNS”, ACS Chem. Neuroscience 2020, 11, 2450-63. https://pubmed.ncbi.nlm.nih.gov/32027110/

     

    Kahl, D; Hutchings, K.M.; Lisabeth, E.M.; Haak, A.J.; Leipprandt, J.R.; Khanna, D.; Tsou, P.-S.; Campbell, P.L.; Fox, D.A.; Wen, B.; Sun, D.; Bailie, M.; Neubig, R.R.; Larsen, S.D. “5-Aryl-1,3,4-oxadiazol-2-ylthioalkanoic Acids: A Highly Potent New Class of Inhibitors of Rho/MRTF/SRF-Mediated Gene Transcription as Potential Antifibrotic Agents for Scleroderma” J. Med. Chem.2019, 62, 4350-69. https://www.ncbi.nlm.nih.gov/pubmed/30951312

     

    Lisabeth, E.M.; Kahl, D.; Gopallawa, I.; Haynes, S.E.; Misek, S.A.; Campbell, P.L.; Dexheimer, T.S.; Khanna, D.; Fox, D.A.; Jin, X.; Martin, B.R.; Larsen, S.D.; Neubig, R.R. “Identification of Pirin as a Molecular Target of the CCG-1423/CCG-203971 Series of Anti-Fibrotic and Anti-Metastatic Compounds” ACS Pharmacol & Trans Science 2019, 2, 92-100. https://pubmed.ncbi.nlm.nih.gov/32039344/

     

    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. https://www.ncbi.nlm.nih.gov/pubmed/30221940

     

    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. https://www.ncbi.nlm.nih.gov/pubmed/29627263

     

    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. https://www.ncbi.nlm.nih.gov/pubmed/29650289

     

    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. https://www.ncbi.nlm.nih.gov/pubmed/28323425

     

    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. https://www.ncbi.nlm.nih.gov/pubmed/28285914

     

    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. https://www.ncbi.nlm.nih.gov/pubmed/27050625

     

    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. https://www.ncbi.nlm.nih.gov/pubmed/27992879

     

    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. https://www.ncbi.nlm.nih.gov/pubmed/24706986

     

    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. https://www.ncbi.nlm.nih.gov/pubmed/22058426

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