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John C. Widen

Summary

  • Over 5 years of experience in medicinal chemistry enabling discovery programs in oncology and neuroscience
  • Expertise in discovery and development of covalent small molecules, CNS-focused drug design, and degraders
  • Contributed to programs across multiple stages of drug discovery including high-throughput screening (HTS), hit-to-lead, and lead optimization
  • Served as chemistry lead on >4 early-stage small molecule discovery projects
  • Management of external CRO teams in chemistry, pharmacology and DMPK
  • Expertise in structure-based drug design (SBDD) and computer-aided drug design (CADD)
  • Contributions to programs at the clinical and late pre-clinical stage resulting in >6 patent applications

Professional Experience

Tenvie Therapeutics (Spin out from Denali Therapeutics), South San Francisco, CA

Senior Scientist, Small Molecule Discovery 3/2024-5/2025


  • Chemistry lead for three early-stage programs in hit- and lead-ID stages
  • Managed multiple CRO chemistry and pharmacology teams to deliver targets and key results
  • Identified novel chemical matter starting points for early drug discovery programs with literature-based/information-driven approaches
  • Designed chemical matter using structure-based drug design (SBDD) and SAR across multiple small molecule drug discovery programs to improve potency, optimize DMPK properties, and enable program progression
  • Utilized computational chemistry tools within Schrödinger suite for molecular modeling, alignments, strain energy calculations, and shape screening
  • Contributed to >6 published and pending patent applications


Denali Therapeutics Inc., South San Francisco, CA

Scientist, Lab Leader, Small Molecule Discovery 5/2022-3/2024


  • Worked within a team to carry out and analyze data from a phenotypic HTS and four DEL screens
  • Designed chemical matter using structure-based drug design (SBDD) and SAR across multiple small molecule drug discovery programs to improve potency, optimize DMPK properties, and enable program progression
  • Collaborated with a cross-functional team to develop PROTAC-transport vehicle conjugates for CNS indications
  • Synthesized compounds for multiple programs, contributing to SAR development
  • Developed chemical probes and assay tools for early discovery programs


Frontier Medicines, South San Francisco, CA

Scientist II, Medicinal Chemistry 11/2020-5/2022


  • Served as chemistry lead responsible for the development of screening strategies for molecular glue/induced proximity small molecule discovery
  • Developed high-throughput chemistry and biochemical methods for the discovery of bioactive covalent inhibitors, PROTACS, and molecular glue degraders
  • Worked within a multi-disciplinary team to rationally design small molecules to optimize for potency, selectivity, and DMPK properties across multiple projects
  • Directed external chemistry resources for early discovery projects
  • Responsible for training and managing a direct report chemistry research assistant


Scientist I, Medicinal Chemistry


  • Assisted with directing external chemistry resources by designing small molecules, planning chemical syntheses, and problem-solving synthetic issues
  • Implemented high-throughput chemistry and experimentation to generate lead chemical series and develop SAR across multiple projects
  • Worked with a multi-disciplinary team to rationally design small molecules to optimize for potency, selectivity, and DMPK properties across multiple projects


Stanford University, Stanford, CA

Postdoctoral Fellow, Department of Pathology, Advisor: Prof. Matthew Bogyo 4/2017-11/2020


  • Designed and synthesized NIR quenched-fluorescent peptidic substrate probes targeting proteases involved in human disease
  • Evaluated quenched-fluorescent substrate probes using fluorogenic substrate assays, cell culture assays, fluorescence microscopy, and in vivo mouse models of cancer
  • Extensive training in protease biology, florescence microscopy, and designing and implementing in vivo cancer models (i.e. IV/PO/RO/IP injections, surgery and dissection, tissue slide preparation, staining etc.)
  • Trained and directed multiple international and domestic graduate students in laboratory techniques, critical thinking skills, data analysis, scientific writing, and scientific communication.


University of Minnesota, Minneapolis, MN

8/2011-4/2017

Graduate Student, Department of Medicinal Chemistry, Advisor: Dr. Daniel A. Harki

Thesis Title: Design and Synthesis of Natural Product-Inspired, Cysteine Reactive Probes toward Inhibition of Transcription Factors and Target Identification Studies


  • Designed and synthesized cysteine reactive small molecule probes based on guaianolide natural products toward inhibition of historically 'undruggable' protein targets
  • Biochemically evaluated cysteine reactive small molecule probes for their interaction and inhibition of the NF-KB transcription factor p65/RelA using kinetic thiol reactivity assays and proteomics
  • Trained in advanced synthetic organic chemistry, biochemical techniques, cell culture assays, and proteomics techniques
  • Trained eight undergraduate and professional students in scientific techniques, data analysis, organic chemistry, synthetic and biological laboratory techniques, and written and oral communication skills


Penford Products Co., Cedar Rapids, IA

Junior Scientist, Research and Development 5/2010-8/2011


  • Synthetically modified complex sugars and proteins derived from corn wet-milling products to create biodegradable, grease resistant materials
  • Developed and tested grease resistant formulations for paper product coating applications
  • Conducted a large scale paper coating trial toward developing a biodegradable, grease resistant paper product

Education


2011-2017 Medicinal Chemistry Ph.D. | University of Minnesota | Department of Medicinal Chemistry

2006-2010 Chemistry B.S., Biology minor | University of Iowa

Publications


  1. Dora Konečná, Petr Výmola, Nikola Ternerová, Barbora Výmolová, Elena Garcia-Borja, Rosana Mateu, Filip Šroubek, Jan Pankrác, John C. Widen, Matthew Bogyo, David Netuka, Petr Bušek, and Aleksi ŠedoMolecularly. Targeted protease-activated probes for visualization of glioblastoma: a comparison with 5ALA. Journal of Neurosurgery 2024, 141, 3, 602.
  2. Franco F. Faucher, Kevin J. Liu, Emily D. Cosco, John C. Widen, Jonathan Sorger, Matteo Guerra, and Matthew Bogyo. Protease Activated Probes for Real-Time Ratiometric Imaging of Solid Tumors. ACS Central Science 2023, 9, 5, 1059.
  3. Christopher M. Richards, Sabrina Jabs, Wenjie Qiao, Lauren Varanese, Michaela Schweizer, Peter R. Mosen, Nicholas M. Riley, James R. Zengel, Ryan A. Flynn, Arjun Rustagi, John C. Widen, Christine E. Peters, Yaw Shin Ooi, Pei-Yong Shi, Ralf Bartenschlager, Matthew Bogyo, Carolyn R. Bertozzi, Catherine A. Blish, Dominic Winter, Claude M. Nagamine, Thomas Braulke, and Jan Carette. The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection. [cite_start]Science 2022, 378, 6615, eabn5648.
  4. Luca Abdel Ghani, Maria V. Yusenko, Daria Frank, Ramkumar Moorthy, John C. Widen, Wolfgang Dörner, Cyrus Khandanpour, Daniel A. Harki, and Karl-Heinz Klempnauer. A synthetic covalent ligand of the C/EBPB transactivation domain inhibits acute myeloid leukemia cells. Cancer Letters, 2022, 530, 170-180.
  5. Kas Steuten, Heeyoung Kim, John C. Widen, Brett M. Babin, Ouma Onguka, Scott Lovell, Oguz Bolgi, Berati Cerikan, Christopher J. Neufeldt, Mirko Cortese, Ryan K. Muir, John M. Bennett, Ruth Geiss-Friedlander, Christoph Peters, Ralf Bartenschlager, and Matthew Bogyo. Challenges for Targeting SARS-CoV-2 Proteases as a Therapeutic Strategy for COVID-19. ACS Infectious Disease, 2020, 7, 6, 1457-1468.
  6. Paul A. Jackson, Henry A. M. Schares, Katherine F. M. Jones, John C. Widen, Dan P. Dempe, Francois Grillet, Matthew E. Cuellar, Michael A. Walters, Daniel A. Harki, Kay M. Brummond. Synthesis of Guaianolide Analogues with a Tunable a-Methylene-y-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity. Journal of Medicinal Chemistry, 2020, 63, 23, 14951-14978.
  7. John C. Widen, Martina Tholen, Joshua J. Yim, Matthew Bogyo. Methods for analysis of near-infrared (NIR) quenched-fluorescent contrast agents in Mouse Models of Cancer. Methods in Enzymology, 2020, 639, 141-166.
  8. John C. Widen, Martina Tholen, Joshua J. Yim, Kerriann M. Casey, Stephen Rogalla, and Matthew Bogyo. AND-gate contrast agents for enhanced fluorescence-guided surgery. Nature Biomedical Engineering, 2021, 5, 264-277.
  9. Jordan A. Naumanna, John C. Widen, Leslie A. Jonart, Maryam Ebadi, Jian Tang, David J. Gordon, Daniel A. Harki, Peter M. Gordon. SN-38 conjugated gold nanoparticles activated by Ewing sarcoma specific mRNAs exhibit in vitro and in vivo efficacy. Bioconjugate Chemistry, 2018, 29, 1111-1118.
  10. John C. Widen, Aaron M. Kempema, Jordan W. Baur, Hannah M. Skopec, Jacob T. Edwards, Tenley J. Brown, Dennis A. Brown, Frederick A. Meece, and Daniel A. Harki. Helenalin Analogues Targeting NF-KB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles. ChemMedChem, 2018, 13, 4, 303-311. To see invited cover art: http://onlinelibrary.wiley.com/doi/10.1002/cmdc.v13.4/issuetoc
  11. Anand Divakarana, Siva K. Tallurib, Alex M. Ayoubb, Neeraj K. Mishrab, Huarui Cuib, John C. Widen, Norbert Berndt, Jin-Yi Zhu, Ernst K. Schonbrunn, Daniel A. Harki, William C.K. Pomerantz. 1,4,5 Trisubstituted Imidazoles as Domain-1 Selective BET-Bromodomain Inhibitors. Journal of Medicinal Chemistry, 2018, 61, 9316-9334. [cite: 88, 89]
  12. John C. Widen, Aaron M. Kempema, Peter W. Villalta, and Daniel A. Harki. Targeting NF- p65 with a Helenalin Inspired Bis-electrophile. ACS Chemical Biology, 2017, 12, 102-113.
  13. Paul Arthur Jackson, John C. Widen, Daniel A. Harki, and Kay M. Brummond. Covalent Modifiers: A Chemical Perspective on the Reactivity of a, -Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions. [cite_start]Journal of Medicinal Chemistry, 2017, 60, 839-885.
  14. Sarah M. Wells, John C. Widen, Daniel A. Harki, and Kay M. Brummond. Alkyne Ligation Handles: Propargylation of Hydroxyl, Sulfhydryl, Amino and Carboxyl Groups via the Nicholas Reaction. Organic Letters, 2016, 18, 18, 4566-4569.
  15. Aaron M. Kempema, John C. Widen, Joseph K. Hexum, Timothy E. Andrews, Dan Wang, Susan K. Rathe, Frederick A. Meece, Klara Noble, David A. Largaespada, and Daniel A. Harki. Synthesis and Antileukemic Activities of C1-C10-Modified Parthenolide Analogues. [cite_start]Bioorganic and Medicinal Chemistry, 2015, 23, 4737-4745.
  16. Bo Wen, Joseph K. Hexum, John C. Widen, Daniel A. Harki, and Kay M. Brummond. A Redox Economical Synthesis of Bioactive 6,12-Guaianolides. Organic Letters, 2013, 15, 11, 2644-2647.
  17. Pradeep P. Kapadia, John C. Widen, Mackenzie A. Magnus, Dale C. Swenson, and F. Christopher Pigge. Tetrapyridyl Tetraphenylethylenes: Supramolecular Building Blocks with Aggregation-Induced Emission Properties. [cite_start]Tetrahedron Letters, 2011, 52, 2519-2522.

Patents


  1. WO2025024329, Preparation of pyrrolopyrimidine compounds, compositions, and methods for use as TRPML1 modulators.
  2. WO2025019357, Preparation of azolylaryl carboxamides and related compounds as SARM1 inhibitors, compositions, and methods of use
  3. WO2024216209, Preparation of 1-(1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide compounds, compositions, and methods.
  4. WO2024130166, Preparation of heterocyclic compounds as SARM1 inhibitors
  5. WO2024108155, Synthesis of azaspiro heterocylic prodrugs as transmembrane protein modulators treating cancers, neurodegenerative, inflammatory, or lysosomal storage disorders.
  6. WO2024108147, Azolecarboxamide compounds as ion channel modulators, compositions, and methods for preparation.
  7. WO2023081840, Pyridinopyrimidines and piperidinopyrimidines as KRAS G12C inhibitors and their preparation.
  8. Patent Filing No. 62/745809, Multi-Enzyme Activated Imaging Probes and Related Compositions and Methods.
  9. Patent No. 20120125231, Coating Formulation. [cite: 118]

Scholarships and Awards


2019 American Cancer Society-Grandview League Research Funding Initiative Postdoctoral Award PF-19-105-01-CCE (Award #: 133106)

2019 Ruth L. Kirshstein Individual National Research Service Award (F32) National Institute of Health, National Institute of Biomedical Imaging and Bioengineering (Turned down for American Cancer Society Postdoctoral Fellowship Award)

2014 Travel Grant from the American Chemical Society Division of Biological Chemistry 248th National ACS meeting | San Francisco, CA (Oral Presentation)

2013 Bighley Fellowship | University of Minnesota

2006-2010 Honor Student | University of Iowa

2009 The Chemistry Alumni Sophomore Award | University of Iowa

2008 Russel K. Simms Scholarship | University of Iowa

Presentations and Seminars


  1. Pacific Coast Protease Workshop, Borega Springs, CA (2025). Design Principles of CNS Drug Discovery and Careers in Biotech
  2. Professional Development Retreat, University of Minnesota, Department of Medicinal Chemistry, Minneapolis, MN (2024). A Journey in Biotech.
  3. Special Seminar, hosted by Jan Konvalinka: Institute of Organic Chemistry and Biochemistry, Prague, Czech Republic (2019). Multivariate 'AND-gate' Substrate Probes as Enhanced Contrast Agents for Fluorescence guided Surgery.
  4. Junior Scientist Workshop on Solving Biological Problems with Chemistry: Janelia Research Campus, Ashburn, Virginia (2019). Dual Quenched Protease Substrates for Optically Guided Tumor Resections.
  5. Pacific Coast Protease Spring Conference: Borrego Springs, CA (2019). Dual quenched protease substrates for optically guided tumor resections.
  6. Proteolytic Enzymes and Their Inhibitors, Gordon Research Conference: Ciocco, Barga, Italy (2018). Dual Protease Triggered AND-Gate Probe for Targeted Imaging of Tumors In Vivo.
  7. Stanford University ChEM-H Department Postdoctoral Retreat: Sonoma, CA (2018). A Dual Protease Triggered AND-Gate Probe for Targeted Imaging of Tumors In Vivo.
  8. 54th Annual MIKI Medicinal Chemistry Meeting; Iowa City, IA (2016). Development of Cysteine Reactive Probes Towards p65/RelA of the NF-KB Pathway.
  9. 248th American Chemical Society Fall National Meeting, Biological Chemistry Graduate Student and Postdoctoral Research Symposium; San Francisco, CA (2014). Natural Product Inspired Alkyne Probes with Cysteine Reactive Exocyclic Methylene Butyrolactones.