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.

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.

Abstract: Cancer cells have developed uncanny strategies to evade the effectiveness of anticancer therapies and immune destruction by modulating their energy metabolism to a pro-survival state. This altered metabolism supports their proliferation and enables niches to thrive even in the presence of unfavorable conditions. 

The glycolytic and the mitochondrial-mediated energy generation pathways represent some of the most dysregulated energy pathways in tumorigenesis. Metabolic profiling has shown the upregulation of glycolysis, oxidative phosphorylation, and the dual dependence of most cancers on both pathways for energy, in a need-dependent manner. 

Here, I report on strategies that leverage the multiple energy pathway dependence of triple-negative breast cancer (TNBC) as a therapeutic approach; identify a novel energy metabolism-perturbing therapeutic target; and elucidate the role of endogenous and exogenous mitochondrial perturbation in breast cancer metastasis and progression. 

The excessive energy demand of the highly proliferative TNBC is a crucial driver of metabolic plasticity. I hypothesized that targeting multiple metabolic pathways in a dual-therapy approach in cancer will provide a profound exploitation of metabolic vulnerabilities for efficacious treatment regimens. Thus, I leveraged this energy gluttony to develop a strategy that targets both glycolysis and oxidative phosphorylation, using 2-deoxyglucose (2DG), a hexokinase (HK) inhibitor, and an OXPHOS-targeting gold(III) anticancer agent, respectively.

The in vivo anticancer response demonstrated improved synergy. However, the non-specificity of 2DG in targeting hexokinase led to a specific CRISPR-Cas9-mediated manipulation of HK1, HK2, and HK3 respectively in TNBC cells. Further rigorous target validation studies culminated in the identification of HK3 as a promising therapeutic target in TNBC, revealing it to be a previously uncharacterized and markedly understudied isoform. 

In efforts to glean more insights into cancer energy metabolism and the mitochondrial-modulatory potency of gold(III) complexes, I validated the antitumorigenic, antimetastatic and energy stress-inducing effects of targeting voltage-dependent anion channels 1 (VDAC1), the main regulator of metabolite flux between mitochondria and cytosol, in TNBC using various in vitro and in vivo models. 

Exogenous mitochondria transfer, a term that describes the trafficking of mitochondria from external donors to cancer cells, has gained traction as an emerging concept in cancer energy metabolism. To further our understanding of this concept, I have shown that cancer cells hijack the mitochondria of immune cells, resulting in depletion of metabolic energy available to the immune cells. This study identifies a new therapeutic target and unveils new insight into our understanding of targeting energy metabolism in cancer.

Abstract: Cancer cells have developed uncanny strategies to evade the effectiveness of anticancer therapies and immune destruction by modulating their energy metabolism to a pro-survival state. This altered metabolism supports their proliferation and enables niches to thrive even in the presence of unfavorable conditions. 

The glycolytic and the mitochondrial-mediated energy generation pathways represent some of the most dysregulated energy pathways in tumorigenesis. Metabolic profiling has shown the upregulation of glycolysis, oxidative phosphorylation, and the dual dependence of most cancers on both pathways for energy, in a need-dependent manner. 

Here, I report on strategies that leverage the multiple energy pathway dependence of triple-negative breast cancer (TNBC) as a therapeutic approach; identify a novel energy metabolism-perturbing therapeutic target; and elucidate the role of endogenous and exogenous mitochondrial perturbation in breast cancer metastasis and progression. 

The excessive energy demand of the highly proliferative TNBC is a crucial driver of metabolic plasticity. I hypothesized that targeting multiple metabolic pathways in a dual-therapy approach in cancer will provide a profound exploitation of metabolic vulnerabilities for efficacious treatment regimens. Thus, I leveraged this energy gluttony to develop a strategy that targets both glycolysis and oxidative phosphorylation, using 2-deoxyglucose (2DG), a hexokinase (HK) inhibitor, and an OXPHOS-targeting gold(III) anticancer agent, respectively.

The in vivo anticancer response demonstrated improved synergy. However, the non-specificity of 2DG in targeting hexokinase led to a specific CRISPR-Cas9-mediated manipulation of HK1, HK2, and HK3 respectively in TNBC cells. Further rigorous target validation studies culminated in the identification of HK3 as a promising therapeutic target in TNBC, revealing it to be a previously uncharacterized and markedly understudied isoform. 

In efforts to glean more insights into cancer energy metabolism and the mitochondrial-modulatory potency of gold(III) complexes, I validated the antitumorigenic, antimetastatic and energy stress-inducing effects of targeting voltage-dependent anion channels 1 (VDAC1), the main regulator of metabolite flux between mitochondria and cytosol, in TNBC using various in vitro and in vivo models. 

Exogenous mitochondria transfer, a term that describes the trafficking of mitochondria from external donors to cancer cells, has gained traction as an emerging concept in cancer energy metabolism. To further our understanding of this concept, I have shown that cancer cells hijack the mitochondria of immune cells, resulting in depletion of metabolic energy available to the immune cells. This study identifies a new therapeutic target and unveils new insight into our understanding of targeting energy metabolism in cancer.

Abstract: The endoplasmic reticulum (ER) chaperone, glucose-regulated protein (GRP78)/binding immunoglobulin protein (BiP)/HSPA5, is a master regulator of Proteostasis, regulating protein folding, the Unfolded Protein Response (UPR) and Endoplasmic Reticulum-associated degradation (ERAD). GRP78 is often overexpressed in many cancers, and this vulnerability has been therapeutically targeted, but therapeutic success has been hampered by resistance and immunosuppression. Despite the availability of a few inhibitors of GRP78, none have achieved clinical approval, highlighting a critical need for new therapeutic strategies. 

Further, the scaffolding functions of GRP78 remain underexplored, and its potential role as a client hub that promotes resistance is not well understood. Targeting ER resident proteins such as GRP78 for degradation remains a significant challenge, as they are largely inaccessible to current targeted degradation approaches. Here, I report the development of peptidomimetic degraders as first-in-class small molecule scaffolds designed to engage the substrate-binding domain of ER chaperone GRP78 and initiate its selective degradation via the endogenous ER-associated degradation (ERAD) pathway. 

Using integrated computational, biochemical, cellular, and multi-omic approaches, my research shows that these peptidomimetic degraders reshape GRP78/BiP conformational dynamics to promote organelle-localized ligase recruitment and proteostatic clearance. Our lead peptidomimetic degrader of GRP78, SGA01 induces ER stress activating the UPR. SGA01 also exhibits favorable metabolic and plasma stability, demonstrates robust pharmacodynamic kinetics with tumor growth suppression in triple-negative breast cancer models, and has no off-target effects. Together, these findings establish a chemical strategy for enforcing ER-restricted protein degradation and provide a tractable framework for targeting chaperone addiction across various malignancies. 

These GRP78 degraders further elucidated the molecular consequences of GRP78 depletion, including disruption of mitochondrial function and ER-mitochondria crosstalk. SGA01-induced degradation of GRP78 causes ER stress, and uncontrolled ER stress amplifies beyond the ER to the mitochondria, leading to disruption of ER mitochondrial crosstalk and mitochondrial dysfunction. SGA01-based probes were designed to map GRP78 protein interactions. In addition to the dipeptide-based peptidomimetic, further development efforts have extended to tripeptides to elucidate the binding rules governing GRP78 degradation. 

In conclusion, we provided a framework for GRP78-targeted degradation using small-molecule peptidomimetics and elucidated the impact of this degradation on other organelles, such as mitochondria, and its relevance in disease models. 

Abstract: The endoplasmic reticulum (ER) chaperone, glucose-regulated protein (GRP78)/binding immunoglobulin protein (BiP)/HSPA5, is a master regulator of Proteostasis, regulating protein folding, the Unfolded Protein Response (UPR) and Endoplasmic Reticulum-associated degradation (ERAD). GRP78 is often overexpressed in many cancers, and this vulnerability has been therapeutically targeted, but therapeutic success has been hampered by resistance and immunosuppression. Despite the availability of a few inhibitors of GRP78, none have achieved clinical approval, highlighting a critical need for new therapeutic strategies. 

Further, the scaffolding functions of GRP78 remain underexplored, and its potential role as a client hub that promotes resistance is not well understood. Targeting ER resident proteins such as GRP78 for degradation remains a significant challenge, as they are largely inaccessible to current targeted degradation approaches. Here, I report the development of peptidomimetic degraders as first-in-class small molecule scaffolds designed to engage the substrate-binding domain of ER chaperone GRP78 and initiate its selective degradation via the endogenous ER-associated degradation (ERAD) pathway. 

Using integrated computational, biochemical, cellular, and multi-omic approaches, my research shows that these peptidomimetic degraders reshape GRP78/BiP conformational dynamics to promote organelle-localized ligase recruitment and proteostatic clearance. Our lead peptidomimetic degrader of GRP78, SGA01 induces ER stress activating the UPR. SGA01 also exhibits favorable metabolic and plasma stability, demonstrates robust pharmacodynamic kinetics with tumor growth suppression in triple-negative breast cancer models, and has no off-target effects. Together, these findings establish a chemical strategy for enforcing ER-restricted protein degradation and provide a tractable framework for targeting chaperone addiction across various malignancies. 

These GRP78 degraders further elucidated the molecular consequences of GRP78 depletion, including disruption of mitochondrial function and ER-mitochondria crosstalk. SGA01-induced degradation of GRP78 causes ER stress, and uncontrolled ER stress amplifies beyond the ER to the mitochondria, leading to disruption of ER mitochondrial crosstalk and mitochondrial dysfunction. SGA01-based probes were designed to map GRP78 protein interactions. In addition to the dipeptide-based peptidomimetic, further development efforts have extended to tripeptides to elucidate the binding rules governing GRP78 degradation. 

In conclusion, we provided a framework for GRP78-targeted degradation using small-molecule peptidomimetics and elucidated the impact of this degradation on other organelles, such as mitochondria, and its relevance in disease models. 

Abstract: Organic semiconductors, derived from π-conjugated polymers and molecules, enable the development of deformable, stretchable and flexible electronics due to  their tunable redox, optical, electronic and mechanical properties. However, an informed understanding of how multi-scale morphological characteristics of the polymeric and molecular semiconductors influence bulk properties that contribute to electronic and optical performance, especially under operational thermal and mechanical stresses, remains incomplete. 

This lack of understanding poses a challenge to scalability and commercialization of organic electronics. This dissertation develops and deploys computational modeling approaches, particularly atomistic molecular dynamics (MD) simulations, to investigate the multiscale morphological behavior of these synthetic semiconducting materials in the context of thermomechanical stability.

Herein, electron-donating π-conjugated polymers and electron-accepting molecules — systems that are used in combination to develop bulk heterojunction (BHJ) organic semiconductors — are modeled as their neat phases and as blends to elucidate expectations regarding their thermomechanical behavior as they traverse operational thermal and mechanical processes. 

By systematically modeling these organic semiconductors over time and length scales that approach experiments, this dissertation fits into the larger quest for how local (or long-range) molecular morphology, beginning from molecular structural compositions, dictate thermomechanical behavior, thus providing valuable design and processing principles in the bid for electronically efficient, mechanically robust and manufacture-scale organic electronics.

Abstract: Organic semiconductors, derived from π-conjugated polymers and molecules, enable the development of deformable, stretchable and flexible electronics due to  their tunable redox, optical, electronic and mechanical properties. However, an informed understanding of how multi-scale morphological characteristics of the polymeric and molecular semiconductors influence bulk properties that contribute to electronic and optical performance, especially under operational thermal and mechanical stresses, remains incomplete. 

This lack of understanding poses a challenge to scalability and commercialization of organic electronics. This dissertation develops and deploys computational modeling approaches, particularly atomistic molecular dynamics (MD) simulations, to investigate the multiscale morphological behavior of these synthetic semiconducting materials in the context of thermomechanical stability.

Herein, electron-donating π-conjugated polymers and electron-accepting molecules — systems that are used in combination to develop bulk heterojunction (BHJ) organic semiconductors — are modeled as their neat phases and as blends to elucidate expectations regarding their thermomechanical behavior as they traverse operational thermal and mechanical processes. 

By systematically modeling these organic semiconductors over time and length scales that approach experiments, this dissertation fits into the larger quest for how local (or long-range) molecular morphology, beginning from molecular structural compositions, dictate thermomechanical behavior, thus providing valuable design and processing principles in the bid for electronically efficient, mechanically robust and manufacture-scale organic electronics.

Abstract: Graphitic materials possess unique properties due to the unique combination of layered crystalline structure and carbon’s low atomic weight. High performance carbon fiber is one such example, displaying exceptional strength-to-weight ratios, stiffness and thermal and chemical resistance. These properties render high performance carbon fiber a critical structural reinforcement material in the manufacture of composites across industries, including automotive and aerospace applications. Balancing fiber performance with precursor and processing costs, however, remains a challenge. As alternative carbonaceous feedstocks are explored, coal has gained interest for use in graphitic products as a relatively abundant and low-cost source of aromatic carbon.

This work broadly covers the process of using coal for high performance carbon fiber. First, coal extracts are obtained through direct coal liquefaction in petroleum-derived fluid catalytic cracking decant oil. The efficacy of the process and the suitability of the coal extract as a precursor to graphitic products is assessed through comprehensive solubility testing, chemical and thermal characterization and polarized optical microscopy. The thermal conversion of coal extracts to mesophase pitch is then examined, and process development, optimization and methods for real-time reaction progress monitoring are described. Additionally, a general framework for understanding the isotropic-mesophase phase transition from a colloidal perspective is proposed. 

The production of high performance carbon fiber from a coal extract-derived mesophase pitch is then successfully demonstrated, and mesophase pitch properties impacting melt-spinning stability are discussed. Finally, coal contribution to carbon fiber was quantitatively determined via stable carbon isotope analysis. The investigations detailed in this work provide in-depth understanding of co-processing coal and decant oil system via direct coal liquefaction, the impact of processing steps on chemical and material properties, mesophase pitch processability and carbon fiber performance.

Abstract: Graphitic materials possess unique properties due to the unique combination of layered crystalline structure and carbon’s low atomic weight. High performance carbon fiber is one such example, displaying exceptional strength-to-weight ratios, stiffness and thermal and chemical resistance. These properties render high performance carbon fiber a critical structural reinforcement material in the manufacture of composites across industries, including automotive and aerospace applications. Balancing fiber performance with precursor and processing costs, however, remains a challenge. As alternative carbonaceous feedstocks are explored, coal has gained interest for use in graphitic products as a relatively abundant and low-cost source of aromatic carbon.

This work broadly covers the process of using coal for high performance carbon fiber. First, coal extracts are obtained through direct coal liquefaction in petroleum-derived fluid catalytic cracking decant oil. The efficacy of the process and the suitability of the coal extract as a precursor to graphitic products is assessed through comprehensive solubility testing, chemical and thermal characterization and polarized optical microscopy. The thermal conversion of coal extracts to mesophase pitch is then examined, and process development, optimization and methods for real-time reaction progress monitoring are described. Additionally, a general framework for understanding the isotropic-mesophase phase transition from a colloidal perspective is proposed. 

The production of high performance carbon fiber from a coal extract-derived mesophase pitch is then successfully demonstrated, and mesophase pitch properties impacting melt-spinning stability are discussed. Finally, coal contribution to carbon fiber was quantitatively determined via stable carbon isotope analysis. The investigations detailed in this work provide in-depth understanding of co-processing coal and decant oil system via direct coal liquefaction, the impact of processing steps on chemical and material properties, mesophase pitch processability and carbon fiber performance.