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

  • January 1, 2023 - November 30, 2027 - Development of caspase-6 inhibitors for treatment of NASH , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DK135289
  • April 1, 2021 - May 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
  • April 6, 2021 - March 31, 2026 - Evolution and inhibition of carbapenemase in beta-lactam resistance , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI161762
  • 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
  • September 30, 2023 - February 28, 2025 - Optimizing brain penetrance of caspase-6 inhibitors to treat neurodegenerative diseases , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R41AG078036
  • 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. Ponnusamy V, Randall DR, Lee ZH, Das NK, Zhao L, Buscher K, Solanki S, Renslo AR, Hsu PP, Shah YM Labile iron pool dynamics do not drive ferroptosis potentiation in colorectal cancer cells.  View on PubMed
  2. Klope MT, Talukder P, Blank BR, Chelebieva S, Chen J, Fontaine SD, Gonciarz RL, Jaishankar P, Lee GJ, Legac J, Mathur V, Narayan A, Okitwi M, Orena S, Settineri NS, Tapia JA, Taremwa Y, Tumwebaze PK, Vinod A, Burrows JN, Rosenthal PJ, Cooper RA, Renslo AR Identifying a next-generation antimalarial trioxolane in a landscape of artemisinin partial resistance.  View on PubMed
  3. Flowers J, Echols N, Correy GJ, Jaishankar P, Togo T, Renslo AR, van den Bedem H, Fraser JS, Wankowicz SA. Expanding automated multiconformer ligand modeling to macrocycles and fragments. Elife. 2025 Jun 30; 14.  View on PubMed
  4. Maciag AE, Yang Y, Sharma AK, Turner DM, DeHart CJ, Abdelkarim H, Fan L, Smith BP, Kumari V, Dyba M, Rigby M, Castillo Badillo JA, Adams L, Fornelli L, Fox S, Brafman A, Turbyville T, Gillette W, Messing S, Agamasu C, Wolfe AL, Gysin S, Chan AH, Simanshu DK, Esposito D, Chertov O, Stephen AG, Arkin M, Renslo A, Kelleher NL, Gaponenko V, Lightstone FC, Nissley DV, McCormick F. Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine. Proc Natl Acad Sci U S A. 2025 May 13; 122(19):e2410766122.  View on PubMed
  5. Flowers J, Echols N, Correy G, Jaishankar P, Togo T, Renslo AR, van den Bedem H, Fraser JS, Wankowicz SA. Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments. bioRxiv. 2025 Apr 30.  View on PubMed
  6. Detomasi TC, Degotte G, Huang S, Suryawanshi RK, Diallo A, Lizzadro L, Zapatero-Belinchón FJ, Taha TY, Li J, Richards AL, Hantz ER, Alam Z, Montano M, McCavitt-Malvido M, Gumpena R, Partridge JR, Correy GJ, Matsui Y, Charvat AF, Glenn IS, Rosecrans J, Revalde JL, Anderson D, Hultquist JF, Arkin MR, Neitz RJ, Swaney DL, Krogan NJ, Shoichet BK, Verba KA, Ott M, Renslo AR, Craik CS. Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus MPro inhibitors with potent in vivo efficacy. Sci Adv. 2025 04 25; 11(17):eadt7836.  View on PubMed
  7. Klope MT, Tapia Cardona JA, Chen J, Gonciarz RL, Cheng K, Jaishankar P, Kim J, Legac J, Rosenthal PJ, Renslo AR. Synthesis and In Vivo Profiling of Desymmetrized Antimalarial Trioxolanes with Diverse Carbamate Side Chains. ACS Med Chem Lett. 2024 Oct 10; 15(10):1764-1770.  View on PubMed
  8. Deal PE, Lee H, Mondal A, Lolicato M, Mendonça PRF, Black H, Jang S, El-Hilali X, Bryant C, Isacoff EY, Renslo AR, Minor DL. Development of covalent chemogenetic K2P channel activators. Cell Chem Biol. 2024 Jul 18; 31(7):1305-1323.e9.  View on PubMed
  9. Pezacki AT, Gonciarz RL, Okamura T, Matier CD, Torrente L, Cheng K, Miller SG, Ralle M, Ward NP, DeNicola GM, Renslo AR, Chang CJ. A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools. Proc Natl Acad Sci U S A. 2024 Jul 09; 121(28):e2401579121.  View on PubMed
  10. Deal PE, Lee H, Mondal A, Lolicato M, de Mendonca PRF, Black H, El-Hilali X, Bryant C, Isacoff EY, Renslo AR, Minor DL. Development of covalent chemogenetic K2P channel activators. bioRxiv. 2023 Oct 18.  View on PubMed
  11. 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 11 16; 30(11):1468-1477.e6.  View on PubMed
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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 02 28; 42(2):112058.  View on PubMed
  20. 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

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