Thomas Hanigan

Thomas Hanigan

he/him/his

Harnessing Metabolism for Drug Development

Research Projects

Copy number alterations disrupt mitochondrial metabolism.

January 04, 2024

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.

Nucleophilic stress through proline catabolism.

January 03, 2024

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).

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

January 02, 2024

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.