Thomas Hanigan

Thomas Hanigan

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Harnessing Metabolism for Drug Development

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NGS

Published:

Common protocols for WGS and RNA sequencing

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High-Content Imaging

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Common protocols for image-based assays measuring cell cycle, replication, mitochondria and plasma membrane dynamics and metabolic flux

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Team

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Research Technicians

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publications

Divergent JNK Phosphorylation of HDAC3 in Breast Cancer Cells Determines HDAC Inhibitor Binding and Selectivity

Published in Cell Chemical Biology, 2017

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.

Recommended citation: 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.
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Structurally Diverse Histone Deacetylase Photoreactive Probes: Design, Synthesis, and Photolabeling Studies in Live Cells and Tissue.

Published in Chem Med Chem, 2019

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.

Recommended citation: 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
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Structurally Diverse Histone Deacetylase Photoreactive Probes: Design, Synthesis, and Photolabeling Studies in Live Cells and Tissue.

Published in J Biol Methods, 2019

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.

Recommended citation: 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.
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ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth. Nat Chem Biol 17, 856–864 (2021).

Published in Nature Chemical Biology, 2021

Significance: Discovery of first in class inhibitors ABHD17, which selectively block depalmitoylation of N-Ras in a plasma membrane-specific fashion.

Recommended citation: 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).
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Proteomic discovery of chemical probes that perturb protein complexes in human cells

Published in Molecular Cell, 2023

Novel function-first approach to discover molecules that disrupt multi-protein complexes, with focus on the splicing machinery

Recommended citation: 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
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Small Molecule Inhibitors of Complex IV Induce Imbalanced Pyrimidine Expansion in OXA1L Variant Cells

Published in Preprint, 2024

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.

Recommended citation: 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)..
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talks

Combinatorial strategies to synthesize small molecule libraries and chemical probes for allosteric enzymes.

Published:

To balance biosynthesis and bioenergetic homeostasis, adenine nucleotides are incorporated into numerous intermediary amino acids, proteins, lipids, carbohydrates, and vitamins, which function as orthosteric substrates and cofactors, and/or allosteric ligands that can activate catabolic enzymes when energy levels are depleted. This type of metabolic regulation through combination extends far beyond adenine nucleotides. In this project, we will use structure-based drug design, combinatorial chemistry and photoaffinity labeling to synthesize small molecule libraries biased towards allosteric catabolic enzymes and develop chemical proteomic platforms to delineate functional liganding events that modulate metabolic flux for treatment of metabolic disease.

Nucleophilic stress through proline catabolism.

Published:

Within the proline metabolic pathway (Figure 2a), loss-of-function ALDH4A1 mutations result in the accumulation of its nucleophilic substrate pyrroline-5-carboxylate (P5C), which depletes the essential cofactor pyridoxal-5’-phosphate (PLP) through Knoevenagel condensation, causing selective cytotoxicity to cells of the central nervous system and connective tissue (Figure 2b). Conversely, biallelic mutations in ALDH18A1 result in proline auxotrophy and toxicity to the same tissue. We have identified a recurrent deletion that alters proline metabolism in ~15-55% of prostate, skin and central nervous system cancers (Figure 3c). This project focuses on developing chemical-proteomic and imaging based platforms to screen small molecule libraries for compounds that alter nucleophilic stress through proline metabolism (Figure 2d,e).

Copy number alterations disrupt mitochondrial metabolism.

Published:

Focal or arm-level amplification of the oncogene NKX2-1 (chr14q13) and/or loss of heterozygosity at chr14q occurs in 12-53% of lung cancers, and there are currently no molecularly targeted small molecule therapeutics for these alterations. We have recently developed novel compounds targeting the mitochondrial insertase OXA1L, encoded adjacent to NKX2-1 at chr14q11, which is collaterally amplified or deleted along with NKX2-1 across ~10% of samples from The Cancer Genome Atlas. Importantly, these compounds are selectively lethal in NKX2-1 amplified human cancer cell lines, owing to partial inhibition of OxPhos and increased OxPhos-coupled de novo pyrimidine biosynthesis. Based on this mechanism, we seek to validate OXA1L as a target in chr14q amplified and deleted cancer cells and animal models, understand additional vulnerabilities associated with altered pyrmidine biosynthes and further establish structure activity reliationships governing OXA1L inhibitor selectivity.

teaching

Hiring Post-doctoral Researchers

, University of Houston Department of Pharmacological & Pharmaceutical Sciences, 2024

We are actively looking for post-doctoral researchers with experience in multi-component reaction development, kinase inhibitor synthesis, and/or metabolism oriented chemical biology. If interested, please email [email protected] describing how you might fit into one or more of the ongoing lab projects.