CV

Thomas W. Hanigan, Ph.D. Department of Pharmacological and Pharmaceutical Sciences, The University of Houston 4349 Martin Luther King Boulevard Houston, Texas 77204-5000 Tel: (319) 389-5342 Email: [email protected] Orcid: 0000-0003-0752-4707

Education

The Scripps Research Institute 2018-2023 Postdoctoral Associate
The University of Iowa Research Assistant 2018 The University of Illinois 2012-2017 Ph.D. in Medicinal Chemistry
Iowa State University 2007-2012 B.A. in Chemistry
B.S. in Materials Engineering

Research Experience

Postdoctoral Associate Advisement: Benjamin Cravatt, Ph.D. Project 1: Leveraging fully functionalized photoreactive probes for target discovery in KEAP1 mutant cancers Project 2: Characterization of ABHD17 selective depalmitoylase inhibitors Project 3: Design and synthesis of small molecules targeting B-Cells for treatment of autoimmune disease Research Associate, University of Iowa Advisement: Sue Blackwell Ph.D., George Weiner, M.D. Project: Phase 2/3 clinical trial “Checkmate CMP-001-011 Melanoma Study” Internship at Adello Biologics in Chicago Advisement: Hari Ranpura Ph.D., Michelle Zheng Ph.D.
Project: Good Manufacturing Practice (GMP), Identification of PEGylation site modification on GCSF using top-down proteomics Graduate Student Advisement: Pavel Petukhov Ph.D., Jonna Frasor Ph.D. Project 1: Methods for detecting change in catalytic activity of histone deacetylase enzymes Project 2: Methods to identify genomic loci targeted by small molecule histone deacetylase inhibitors Project 3: General synthetic strategy for the development of photoreactive probes based on diverse histone deacetylase inhibitor scaffolds Project 4: Biochemical characterization of class I histone deacetylase subcellular localization and post-translational modification state Undergraduate Advisement: Scott Chumbley, Ph.D. and Alan Russell Ph.D. Iowa State Materials Engineering Project: Noninvasive fatigue crack detection to decrease risk of catastrophic failure of ammonia nurse tanks

Awards and Fellowships

PIIPS Fellowship: American Society for Pharmacology and Experimental Therapeutics 2018 Charles Wesley Petranek Memorial Scholar 2017 UIC Research Day, Cancer center award for best poster 2016 UIC Cancer Center Research Forum, Best Poster Award 2016 W.E. van Doren Scholar 2014 American Association for the Advancement of Science Nominee 2013 Alpha Lambda Delta and Phi Eta Sigma (ALD/PES) National Honors Societies 2013

Presentations

2021 Keystone Tumor Metabolism and the Microenvironment “Small Molecule Inhibition of OXA1L Selectively Kills ZFHX3 Mutant NSCLC from Imbalanced Cytidine Pool Expansion”. Oral Presentation. https://virtual.keystonesymposia.org/ks/sessions/8444/view

2017 UIC Research Day “Divergent Phosphorylation of Histone Deacetylase in Breast Cancer Determines Inhibitor Binding and Selectivity”, poster

2016 MIKI Medicinal Chemistry Symposium “The Importance of Determining Target Engagement in a Native Environment”, oral presentation

2016 UIC Research Day “Cell Based Strategy to Improve HDAC Inhibitor Efficacy as Breast Cancer Therapeutics”, poster

2015 Cancer Center Research Forum “Cell Based Strategy to Improve HDAC Inhibitor Efficacy as Breast Cancer Therapeutics”, poster

28th Annual ASPET Scientific Meeting, Chicago 2015 “Having a Complex: Implications on HDAC-Ligand Interactions”, poster

7th Yao Yuan Biotech-Pharma Symposium, At the interface of Chemistry and Biology for Drug Discovery, Chicago 2015 “Having a Complex: Implications on HDAC-Ligand Interactions”, poster

ACS chemistry conference, San Francisco 2014 “Optimization of photolabeling and visualization of histone deacetylase 2 in cell lysates”, poster

Publications

Thomas W. Hanigan, Junichiro Takaya, Haoxin Li, Jarret R. Remsberg, Verena Albert, J.C. Ducom, Christopher M. Joslyn, Scott C Henderson, Kathryn S Spencer, Sabrina Barbas, Melissa A Dix, Kim Masuda, Enrique Saez, Kenji Sasaki, Christopher G. Parker, Benjamin F. Cravatt. Small Molecule Inhibitors of Complex IV Induce Imbalanced Pyrimidine Expansion in OXA1L Variant Cells. In-Preparation (2023). Significance: Discovery of first in class small molecules targeting the mitochondrial insertase OXA1L, and characterization of a common genetic vulnerability mediating selective lethality in non-small cell lung cancer. Remsberg, J.R., Suciu, R.M., Zambetti, N.A., Thomas W. Hanigan, et al. ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth. Nat Chem Biol 17, 856–864 (2021). https://doi.org/10.1038/s41589-021-00785-8
Significance: Discovery of first in class inhibitors ABHD17, which selectively block depalmitoylation of N-Ras in a plasma membrane-specific fashion. Michael R. Lazear, Jarrett R. Remsberg, Martin G. Jaeger, Katherine Rothamel, Hsuan-lin Her, Kristen E. DeMeester, Evert Njomen, Simon J. Hogg, Jahan Rahman, Landon R. Whitby, Sang Joon Won, Michael A. Schafroth, Daisuke Ogasawara, Minoru Yokoyama, Garrett L. Lindsey, Haoxin Li, Jason Germain, Sabrina Barbas, Joan Vaughan, Thomas W. Hanigan, Vincent F. Vartabedian, Christopher J. Reinhardt, Melissa M. Dix, Seong Joo Koo, Inha Heo, John R. Teijaro, Gabriel M. Simon, Brahma Ghosh, Omar Abdel-Wahab, Kay Ahn, Alan Saghatelian, Bruno Melillo, Stuart L. Schreiber, Gene W. Yeo, Benjamin F. Cravatt. Proteomic discovery of chemical probes that perturb protein complexes in human cells. Bioarxiv. 2022. https://doi.org/10.1101/2022.12.12.520090 Taha TY, Aboukhatwa SM, Knopp RC, Ikegaki N, Abdelkarim H, Neerasa J, Lu Y, Neelarapu R, Thomas W. Hanigan, Thatcher GRJ, Petukhov PA. Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline Based Histone Deacetylase 8 Selective Inhibitors. ACS Med Chem Lett. 2017 Aug 1;8(8):824-829. doi: 10.1021/acsmedchemlett.7b00126. Thomas W. Hanigan, Jonna Frasor, Pavel Petukhov. “Divergent JNK Phosphorylation of HDAC3 in Breast Cancer Cells Determines HDAC Inhibitor Binding and Selectivity. Cell Chemical Biology. 2017 Nov 16;24(11):1356 1367.e8. doi:10.1016/j.chembiol.2017.08.015. Significance: This work demonstrates that histone deacetylase (HDAC) inhibitor selectivity and efficacy is regulated by HDAC phosphorylation and characterizes a novel pathway catalyzing HDAC3 phosphorylation mediated by c-Jun N-terminal kinase, differentially active across breast cancer subtypes. Thus, the selectivity and efficacy of HDAC inhibitors is cell type-dependent, which is not recapitulated in vitro analysis, and provides a strategy to improve HDAC inhibitor efficacy for breast cancer treatment. Thomas W. Hanigan, Taha Y. Taha, Pavel Petukhov. “Potent Hydroxamic Acid HDAC Inhibitors Re-equilibrate the Subcellular Localization and Post-Translational Modification State of Class I HDACs” PLOS ONE 12(10): e0186620. https://doi.org/10.1371/journal.pone.0186620 Thomas W Hanigan, Jeanne Danes, Taha Taha, Jonna Frasor, Pavel Petukhov. “Histone Deacetylase Inhibitor Based Chromatin Precipitation for Identification of Targeted Genomic Loci”. J Biol Methods. 2018;5(1):e88. doi: 10.14440/jbm.2018.216. Significance: This work describes a novel method applying photoreactive HDAC inhibitors for chromatin immunoprecipitation, which permits characterization of genomic loci specifically targeted by HDAC inhibitors. Thomas W. Hanigan, Aboukhatwa SM, Taha TY, Neerasa J, Ranjan R, El-Bastawissy EE, Elkersh MA, El-Moselhy TF, Frasor J, Mahmud N, McLachlan A, Petukhov PA. Structurally Diverse Histone Deacetylase Photoreactive Probes: Design, Synthesis, and Photolabeling Studies in Live Cells and Tissue. ChemMedChem. 2019 Jun 5;14(11):1096-1107. doi: 10.1002/cmdc.201900114. Significance: In this study we describe a robust synthetic strategy to access chemically diverse photoreactive probes (PRPs), which we used to prepare PRPs based on seven HDAC inhibitor scaffolds. The selectivity of these PRP chemotypes for HDAC isoforms was characterized by biochemical assays and photolabeling experiments in cell lines and mouse liver tissues, relevant for the design of isoform selective HDAC inhibitors. Alan M. Russell; Andrew T Becker, PhD; Leonard S Chumbley, PhD; Darrel A Enyart, B.S.; Brian L Bowersox, B.S.; Thomas W Hanigan, B.S.; Jason L Labbe, B.S.; James S Moran, B.S.; Emily L, Spicher, B.S. “A Survey of Flaws Near Welds Detected by Side-angle Ultrasound Examination of 532 Nurse Tanks.” Journal of Loss Prevention in the Process Industries (2016): 263-272

Patents

Hanigan TW, Frasor J, Petukhov P. (2017). Superior anti-cancer combination of HDAC and JNK/p38 pathway kinase inhibitors as treatment for triple-negative breast cancer. Provisional Application for Patent. Application Number 62/457,244 Hanigan TW, Frasor J, Petukhov P. (2017). Convergent synthetic strategy to synthesis of photoreactive probes and their histone deacetylase target engagement evaluation in live cells. Provisional Application for Patent. Application Number 62/457,251 Hanigan TW, Frasor J, Petukhov P. (2017). HDAC3 Phosphorylation as a Diagnostic Marker for HDAC Inhibitor Efficacy. Provisional Application for Patent. Application Number 62/457,254

Teaching and Mentorship

Research Mentor The Scripps Research Institute, Department of Chemistry La Jolla, CA Postdoctoral fellow Chris Reinhardt Research Mentor University of Illinois, Department of Medicinal Chemistry Chicago, IL Graduate students Luana Macedo (03/2014–08/2014), Yunlong Yu (03/2015–10/2017), Taha Y Taha (03/2016–10/2017) and Shaimaa Mohamed Said Aboukhatwa (10/2016–10/2017) and undergraduate students Nathan Brown (11/2017 – 05/2018) and Amy Choi (12/2013 03/2014) Teaching Assistant University of Illinois Chicago, College of Pharmacy Chicago, IL Pharmacy 332 (Biochemistry), Pharmacy 354 (Pharmacology), Pharmacy 405 (PDAT)

Professional Experience

2018-2023 2013-2017 2013-2016 Guest Editorial Board, ASAPbio
Manuscript reviewer for (5 times in total): Life Science Alliance, Bioorganic & Medicinal Chemistry, PLOS ONE, Analytical and Bioanalytical Chemistry, bioarxiv 2019-present 2014-present

Experimental Expertise

Biological Methods
Immortalized and primary cell culture Whole genome and transcriptome sequencing: variant identification, splicing, and differential expression Mass Spectrometry: Bottom-up proteomics: Data-dependent, quantitative SILAC and TMT Top-down proteomics: PEGylation site identification Metabolic Flux Analysis: 13C-/15N glucose, glutamine, uridine, and ammonia RTPCR (primer design, reverse transcription, DNA amplification)
Protein expression and Purification Enzyme Kinetics (fluorometric/luminescent assays for IC50 and Ki determination) Chromatin immunoprecipitation
Antibody based affinity enrichments Small molecule target identification using chemical proteomics Biorthogonal chemistry
Chemistry Synthetic organic chemistry: photoreactive probes, heterocyclic HDAC inhibitors, lignan analogues Synthetic alterations to natural products: biotinylation of oligopeptide antibiotics derived from Streptomyces.
NMR: 1D NMR experiments (H1, C13, F19, and DEPT), 2D NMR experiments (COSY, HMBS, HSQC) Computer Programming Proficient in Python, R, FORTRAN and MATLAB.