Research Summary

My research group is engaged at the interface of chemistry and biology. As medicinal chemists, we design and synthesize small molecules that modulate disease pathology at the level of the enzyme, cell, and whole animal, with active projects in cancer, infectious disease, and neurodegeneration. Our group also developed a parallel synthetic methodology to produce a library of disulfide 'fragments', thereby enabling cysteine-disulfide (Tethering) screening at UCSF. Finally, we design, synthesize and validate novel small molecule probes for the study of labile ferrous iron in biology and disease. Most recently, we described the first of a new class of activity-based probes for proximity labelling of proteins in an iron-dependent fashion, thus enabling the first chemoproteomic studies of the labile iron 'interactome'.

Research Funding

  • April 6, 2021 - March 31, 2026 - Evolution and inhibition of carbapenemase in beta-lactam resistance , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI161762
  • April 1, 2021 - March 31, 2026 - Understanding Efficacy and Fe(II)-Promoted Activation of 1,2,4-Trioxolanes in Cancer , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA260860
  • July 1, 2021 - March 31, 2025 - Developing a pretargeting strategy to detect Fe(II) for nuclear medicine applications , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EB029429
  • May 29, 2013 - August 31, 2023 - Chemical Methods for Ferrous Iron Dependent Drug Delivery , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI105106
  • February 1, 2019 - January 31, 2021 - Discovery of Novel Antimalarial Leads Targeting Translational Repression in Plasmodium parasites , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI135495
  • March 1, 2018 - January 31, 2021 - Expanding the Chemical Biology of K2P Channels with Selective Cellular and In vivo Probes , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01MH116278
  • December 4, 2017 - November 30, 2019 - Biophysical Fragment Screening and Structure Determination for Class A, B, and D Carbapenemases , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI135489
  • March 1, 2011 - February 28, 2013 - Chemical Methods for Ferrous Iron Targeted Drug Delivery , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI094433
  • January 1, 2009 - December 31, 2011 - Identification of Anti-HIV Lead Compounds Targeting Rev , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R41AI076087

Education

St. Olaf College, Northfield, MN, B.A., 05/1993, Chemistry
Massachusetts Institute of Technology, Ph.D., 05/1998, Organic Chemistry
The Scripps Research Institute, La Jolla, CA, Postdoctoral, 12/2000, Molecular Recognition

Selected Publications

  1. Gonciarz RL, Jiang H, Tram L, Hugelshofer CL, Ekpenyong O, Knemeyer I, Aron AT, Chang CJ, Flygare JA, Collisson EA, Renslo AR. In vivo bioluminescence imaging of labile iron in xenograft models and liver using FeAL-1, an iron-activatable form of D-luciferin. Cell Chem Biol. 2023 Oct 05.  View on PubMed
  2. Foss CA, Renslo AR. Imaging-Selected Host Responses in the Context of Infections. J Infect Dis. 2023 10 03; 228(Suppl 4):S302-S310.  View on PubMed
  3. Konstantinidou M, Visser EJ, Vandenboorn E, Chen S, Jaishankar P, Overmans M, Dutta S, Neitz RJ, Renslo AR, Ottmann C, Brunsveld L, Arkin MR. Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments. J Am Chem Soc. 2023 09 20; 145(37):20328-20343.  View on PubMed
  4. Visser EJ, Jaishankar P, Sijbesma E, Pennings MAM, Vandenboorn EMF, Guillory X, Neitz RJ, Morrow J, Dutta S, Renslo AR, Brunsveld L, Arkin MR, Ottmann C. From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking. Angew Chem Int Ed Engl. 2023 09 11; 62(37):e202308004.  View on PubMed
  5. Fink EA, Bardine C, Gahbauer S, Singh I, Detomasi TC, White K, Gu S, Wan X, Chen J, Ary B, Glenn I, O'Connell J, O'Donnell H, Fajtová P, Lyu J, Vigneron S, Young NJ, Kondratov IS, Alisoltani A, Simons LM, Lorenzo-Redondo R, Ozer EA, Hultquist JF, O'Donoghue AJ, Moroz YS, Taunton J, Renslo AR, Irwin JJ, García-Sastre A, Shoichet BK, Craik CS. Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors. Protein Sci. 2023 08; 32(8):e4712.  View on PubMed
  6. Togo T, Tram L, Denton LG, ElHilali-Pollard X, Gu J, Jiang J, Liu C, Zhao Y, Zhao Y, Zheng Y, Zheng Y, Yang J, Fan P, Arkin MR, Härmä H, Sun D, Canan SS, Wheeler SE, Renslo AR. Systematic Study of Heteroarene Stacking Using a Congeneric Set of Molecular Glues for Procaspase-6. J Med Chem. 2023 07 27; 66(14):9784-9796.  View on PubMed
  7. Van Horn KS, Wang D, Medina-Cleghorn D, Lee PS, Bryant C, Altobelli C, Jaishankar P, Leung KK, Ng RA, Ambrose AJ, Tang Y, Arkin MR, Renslo AR. Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6. J Am Chem Soc. 2023 05 10; 145(18):10015-10021.  View on PubMed
  8. Blank BR, Gut J, Rosenthal PJ, Renslo AR. Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials. ACS Med Chem Lett. 2023 Apr 13; 14(4):493-498.  View on PubMed
  9. Admasu TD, Kim K, Rae M, Avelar R, Gonciarz RL, Rebbaa A, Pedro de Magalhães J, Renslo AR, Stolzing A, Sharma A. Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis. Cell Rep. 2023 Feb 06; 42(2):112058.  View on PubMed
  10. Gonciarz RL, Sakhamuri S, Hooshdaran N, Kumar G, Kim H, Evans MJ, Renslo AR. Elevated labile iron in castration-resistant prostate cancer is targetable with ferrous iron-activatable antiandrogen therapy. Eur J Med Chem. 2023 Mar 05; 249:115110.  View on PubMed
  11. Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko DS, Moroz YS, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS. Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2. Proc Natl Acad Sci U S A. 2023 01 10; 120(2):e2212931120.  View on PubMed
  12. Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko D, Moroz Y, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS. Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 Macrodomain of SARS-CoV-2. bioRxiv. 2022 Jul 28.  View on PubMed
  13. Shimizu H, Renslo AR. Systematic Exploration of Passive Permeability in Tetrapeptides with Hydrogen-Bond-Accepting Amino Acid Side Chains. ChemMedChem. 2022 08 17; 17(16):e202200204.  View on PubMed
  14. Sacco MD, Defrees K, Zhang X, Lawless W, Nwanochie E, Balsizer A, Darch SE, Renslo AR, Chen Y. Structure-Based Ligand Design Targeting Pseudomonas aeruginosa LpxA in Lipid A Biosynthesis. ACS Infect Dis. 2022 07 08; 8(7):1231-1240.  View on PubMed
  15. Hulce KR, Jaishankar P, Lee GM, Bohn MF, Connelly EJ, Wucherer K, Ongpipattanakul C, Volk RF, Chuo SW, Arkin MR, Renslo AR, Craik CS. Inhibiting a dynamic viral protease by targeting a non-catalytic cysteine. Cell Chem Biol. 2022 05 19; 29(5):785-798.e19.  View on PubMed
  16. Jiang H, Muir RK, Gonciarz RL, Olshen AB, Yeh I, Hann BC, Zhao N, Wang YH, Behr SC, Korkola JE, Evans MJ, Collisson EA, Renslo AR. Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors. J Exp Med. 2022 04 04; 219(4).  View on PubMed
  17. Gunderson EL, Bryant C, Bulman CA, Fischer C, Luo M, Vogel I, Lim KC, Jawahar S, Tricoche N, Voronin D, Corbo C, Ayiseh RB, Manfo FPT, Mbah GE, Cho-Ngwa F, Beerntsen B, Renslo AR, Lustigman S, Sakanari JA. Pyrvinium Pamoate and Structural Analogs Are Early Macrofilaricide Leads. Pharmaceuticals (Basel). 2022 Feb 02; 15(2).  View on PubMed
  18. Chen J, Gonciarz RL, Renslo AR. Correction: Expanded scope of Griesbaum co-ozonolysis for the preparation of structurally diverse sensors of ferrous iron. RSC Adv. 2021 Nov 10; 11(58):36625.  View on PubMed
  19. Kemp MT, Nichols DA, Zhang X, Defrees K, Na I, Renslo AR, Chen Y. Mutation of the conserved Asp-Asp pair impairs the structure, function, and inhibition of CTX-M Class A β-lactamase. FEBS Lett. 2021 12; 595(24):2981-2994.  View on PubMed
  20. Chen J, Gonciarz RL, Renslo AR. Expanded scope of Griesbaum co-ozonolysis for the preparation of structurally diverse sensors of ferrous iron. RSC Adv. 2021 Oct 18; 11(54):34338-34342.  View on PubMed

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