Abstract: Master regulatory control programs coordinate genetic activity, metabolic state and stress adaptation across cellular systems. Targeting these programs remains a major challenge in chemical biology due to structural complexity, network redundancy, and context-dependent regulation. Understanding how chemical tools can reprogram interwoven regulatory layers is essential for overcoming limitations of current therapeutic strategies.
This dissertation examines how small molecules can modulate two interconnected master regulators: the transcription factor MYC and the mitochondrion. MYC is a protein that regulates the transcription of about 15% of genes in the body, while the mitochondrion is the central organelle governing bioenergetic and redox homeostasis, both of which are frequently altered in inflammatory states.
MYC drives numerous human cancers and represents a viable yet historically intractable target due to its intrinsically disordered structure and lack of a defined binding pocket. Many MYC inhibitors fail because reversible interactions are insufficient to stabilize engagement of this unstable protein.
To address this challenge, I developed multiple strategies to achieve functional chemical engagement of MYC. An in-house platform termed Metal-mediated Affinity Chemistry enabled proximity-guided, site-selective targeting of MYC. The known MYC-MAX disruptor 10058-F4 was conjugated to an Au(III)-based warhead capable of chemo-selective cysteine modification within intrinsically disordered regions, stabilizing small-molecule-MYC interaction and enhancing potency without reliance on conventional pocket binding.
In parallel, through the development of MY05, I established direct intracellular inhibition of MYC. MY05 selectively disrupts MYC-MAX heterodimerization and attenuates MYC-dependent transcriptional programs in cancer models, demonstrating that intrinsically disordered transcription factors can be chemically engaged with meaningful functional consequences. MY05 also provides a chemical framework for the subsequent development of potent covalent modifiers and degraders of MYC.
To extend beyond direct inhibition, complementary approaches were pursued to regulate MYC indirectly through its upstream biochemical control. Targeting HMOX2 revealed a chemical axis that promotes MYC depletion while simultaneously modulating mitochondrial function and redox balance. These findings uncover a mechanistic interface between mitochondrial metabolism and oncogenic transcription, demonstrating that bioenergetic state influences MYC-dependent gene expression.
Chemical perturbation of mitochondrial function was shown to reprogram metabolic states and selectively challenge disease-associated phenotypes. Mitochondria thus function as regulatory nexuses capable of reshaping proliferative and inflammatory signaling networks.
Building on this intersection, direct modulation of mitochondrial regulatory programs was investigated in inflammatory contexts. A brain-penetrant Au(III)-based compound, AuPhos, induced mitochondrial biogenesis, enhanced oxidative capacity, regulated inflammatory signaling and promoted coordinated transcriptional remodeling. In a model of traumatic brain injury, mitochondrial enhancement supported molecular programs associated with metabolic resilience and tissue repair.
Collectively, this work establishes a framework for chemical reprogramming of transcriptional and bioenergetic control systems. Through small-molecule MYC engagement, redox-mediated MYC regulation, and mitochondria-driven transcriptional remodeling, these studies define the functional interplay among master regulatory layers. Further elucidation of the MYC-mitochondrial interface may enable precision modulation of cellular state and inform the development of next-generation therapeutics.
